Dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders

ABSTRACT

A compound according to Formula Ia: 
                         
wherein L 1 , G, and R 1  are as described herein.
 
     The present invention relates to novel compounds according to Formula I that antagonize GPR84, a G-protein-coupled receptor that is involved in inflammatory conditions, and methods for the production of these novel compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions by administering a compound of the invention.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/578,979, filed Dec. 22, 2011, the entire disclosure of which isincorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel compounds that antagonize GPR84,a G-protein-coupled receptor that is involved in inflammatoryconditions.

The present invention also provides methods for the production of thesenovel compounds, pharmaceutical compositions comprising these compounds,and methods for the prevention and/or treatment of inflammatoryconditions (for example inflammatory bowel diseases (IBD), rheumatoidarthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonarydisease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonaryfibrosis (IPF))), neuroinflammatory conditions, infectious diseases,autoimmune diseases, endocrine and/or metabolic diseases, and/ordiseases involving impairment of immune cell functions by administeringa compound of the invention.

BACKGROUND OF THE INVENTION

GPR84 was recently isolated and characterized from human B cells(Wittenberger et al., 2001, J Mol Biol, 307, 799-813) as the result ofan expressed sequence tag data mining strategy, and also using adegenerate primer reverse transcriptase-polymerase chain reaction(RT-PCR) approach aimed to identify novel chemokine receptors expressedin neutrophils (Yousefi S et al. 2001 J Leukoc Biol; 69, 1045-52).

GPR84 (also known as EX33) remained an orphan GPCR until theidentification of medium-chain FFAs with carbon chain lengths of 9-14 asligands for this receptor (Wang et al., (2006) J. Biol. Chem.281:3457-64). GPR84 was described to be activated by capric acid(C10:0), undecanoic acid (C11:0) and lauric acid (C12:0) with potenciesof 5 μM, 9 μM and 11 μM, respectively. Two small molecules were alsodescribed to have some GPR84 agonist activity: 3,3′ di-indolylmethane(DIM) (Wang et al. (2006) J. Biol. Chem. 281:3457-64) and embelin (WO2007/027661A2).

GPR84 expression has been shown to be expressed in immune cells at leastbut not limited to polymorphonuclear leukocytes (PMN), neutrophils,monocytes, T cells, B cells. (Wang et al., 2006, The Journal ofBiological Chemistry, 281, 45, 3457-3464, Yousefi et al., 2001, Journalof Leukocyte Biology, 69, 1045-1052, Venkataraman and Kuo, 2005,Immunology Letters, 101, 144-153, WO2007/027661 A2). Higher levels ofGPR84 were measured in neutrophils and eosinophils than in T-cells andB-cells. GPR84 expression was demonstrated in tissues that may play arole in the propagation of the inflammatory response such as lung,spleen, bone marrow.

For example, in a recent review, Du Bois reported the current status oftherapies for lung interstitial diseases, such as idiopathic pulmonaryfibrosis (IPF). There are almost 300 distinct injurious or inflammatorycauses of interstitial lung disease that can result in diffuse lungscarring, and the initial stages of the IPF pathology are very likely toinvolve inflammation (Du Bois, 2010, Nat Rev, Drug Discovery, 9, 129),and combination therapies involving anti-inflammatory treatment could beadvantageously used.

The expression of GPR84 was highly up-regulated in monocytes/macrophagesupon LPS stimulation (Wang et al., 2006, The Journal of BiologicalChemistry, 281, 45, 3457-3464).

GPR84 knock-out (KO) mice are viable and indistinguishable fromwild-type littermate controls (Venkataraman and Kuo, 2005, ImmunologyLetters, 101, 144-153). The proliferation of T and B cells in responseto various mitogens is reported to be normal in GPR84-deficient mice(Venkataraman and Kuo, 2005, Immunology Letters, 101, 144-153). T helper2 (Th2) differentiated T cells from GPR84 KO secreted higher levels ofIL4, IL5, IL13, the 3 major Th2 cytokines, compared to wild-typelittermate controls. In contrast, the production of the Th1 cytokine,INFγ, was similar in Th1 differentiated T cells from GPR84 KO andwild-type littermate (Venkataraman and Kuo, 2005, Immunology Letters,101, 144-153).

In addition, capric acid, undecanoic acid and lauric acid dosedependently increased the secretion of interleukin-12 p40 subunit (IL-12p40) from RAW264.7 murine macrophage-like cells stimulated with LPS. Thepro-inflammatory cytokine IL-12 plays a pivotal role in promotingcell-mediated immunity to eradicate pathogens by inducing andmaintaining T helper 1 (T_(h)1) responses and inhibiting T helper 2(T_(h)2) responses. Medium-chain FFAs, through their direct actions onGPR84, may affect T_(h)1/T_(h)2 balance.

Berry et al. identified a whole-blood 393-gene transcriptional signaturefor active tuberculosis (TB) (Berry et al., 2010, Nature, 466, 973-979).GPR84 was part of this whole-blood 393-gene transcriptional signaturefor active TB indicating a potential role for GPR84 in infectiousdiseases.

GPR84 expression was also described in microglia, the primary immuneeffector cells of the central nervous system (CNS) frommyeloid-monocytic origin (Bouchard et al., 2007, Glia, 55:790-800). Asobserved in peripheral immune cells, GPR84 expression in microglia washighly inducible under inflammatory conditions such as TNFa and IL1treatment but also notably endotoxemia and experimental autoimmuneencephalomyelitis (EAE), suggesting a role in neuro-inflammatoryprocesses. Those results suggest that GPR84 would be up-regulated in CNSnot only during endotoxemia and multiple sclerosis, but also in allneurological conditions in which TNFα or IL1b pro-inflammatory cytokinesare produced, including brain injury, infection, Alzheimer's disease(AD), Parkinson's disease (PD).

GPR84 expression was also observed in adipocytes and shown to beenhanced by inflammatory stimuli (Nagasaki et al., 2012). The resultssuggest that GPR84 emerges in adipocytes in response to TNFα frominfiltrating macrophages and exacerbates the vicious cycle betweenadiposity and diabesity, and therefore the inhibition of GPR84 activitymight be beneficial for the treatment of endocrine and/or metabolicdiseases.

Therefore, the present invention provides novel compounds, processes fortheir preparation and their use in the preparation of a medicament forthe treatment of inflammatory conditions (for example inflammatory boweldiseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g.chronic obstructive pulmonary disease (COPD) and lung interstitialdiseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatoryconditions, infectious diseases, autoimmune diseases, endocrine and/ormetabolic diseases, and/or diseases involving impairment of immune cellfunctions.

SUMMARY OF THE INVENTION

The present invention relates to novel dihydropyrimidinoisoquinolinonecompounds that antagonize GPR84, and that are potentially useful for thetreatment of inflammatory conditions (for example inflammatory boweldiseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g.chronic obstructive pulmonary disease (COPD) and lung interstitialdiseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatoryconditions, infectious diseases, autoimmune diseases, endocrine and/ormetabolic diseases, and/or diseases involving impairment of immune cellfunctions.

The present invention also provides methods for the production of thesecompounds, pharmaceutical compositions comprising these compounds andmethods for treating inflammatory conditions (for example inflammatorybowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases(e.g. chronic obstructive pulmonary disease (COPD) and lung interstitialdiseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatoryconditions, infectious diseases, autoimmune diseases, endocrine and/ormetabolic diseases, and/or diseases involving impairment of immune cellfunctions.

Accordingly, in a first aspect of the invention, a compound of theinvention is disclosed having a Formula Ia:

-   -   wherein    -   R¹ is H, Me, or halo;    -   L₁ is absent or is —O—, —S—, or —NR^(4a)—;    -   G is        -   R²,        -   —W-L₂-R², or        -   —W-L₃-R³    -   W is C₁₋₄ alkylene, C₂₋₄ alkenylene having one double bond, or        C₂₋₄ alkynylene having one triple bond;    -   L₂ is absent or is —O—;    -   R² is        -   H,        -   C₁₋₈ alkyl, optionally substituted with one to three groups            independently selected from            -   OH,            -   halo,            -   CN,            -   C₁₋₆ alkoxy,            -   C₃₋₇ cycloalkyl,            -   4-6 membered heterocycloalkyl comprising one to three                heteroatoms independently selected from S, and O,            -   5-6 membered heteroaryl comprising one to three                heteroatoms independently selected from N, S, and O, and            -   phenyl,        -   C₄₋₇ cycloalkenyl comprising one double bond,        -   5-7 membered heterocycloalkenyl comprising one double bond,            and one to three heteroatoms independently selected from N,            O, and S,        -   C₃₋₇ cycloalkyl optionally substituted with one or more            independently selected R⁵ groups,        -   4-10 membered heterocycloalkyl comprising one to two            heteroatoms independently selected from S, and O, optionally            substituted with one to three independently selected R⁵            groups,        -   5-10 membered heteroaryl comprising one to three heteroatoms            independently selected from N, S, and O, optionally            substituted with one to three independently selected R⁶            groups, or        -   C₆₋₁₀ aryl optionally substituted with one or more            independently selected R⁶ groups;    -   L₃ is —NR^(4b)—;    -   R³ is        -   C₁₋₄ alkyl substituted with            -   C₆₋₁₀ aryl optionally substituted with one or more                independently selected R⁷ groups, or            -   5-10 membered heteroaryl comprising one to three                heteroatoms independently selected from N, S, and O,                optionally substituted with one or more independently                selected R⁷ groups,        -   5-10 membered heteroaryl comprising one to three heteroatoms            independently selected from N, S, and O, optionally            substituted with one or more independently selected R⁷            groups, or        -   C₆₋₁₀ aryl optionally substituted with one or more            independently selected R⁷ groups;    -   Each R^(4a) and R^(4b) is independently selected from H, C₁₋₄        alkyl, and C₃₋₇ cycloalkyl;    -   R⁵ is oxo or R⁶;    -   R⁶ is        -   —OH,        -   halo,        -   —NO₂,        -   C₁₋₆ alkyl optionally substituted with one to three groups            independently selected from halo, and OH,        -   C₁₋₆ alkoxy optionally substituted with one to three groups            independently selected from halo, and OH,        -   C₃₋₇ cycloalkyl,        -   —C(═O)OR⁸,        -   —C(═O)NR⁹R¹⁰,        -   —NHC(═O)—C₁₋₄ alkyl,        -   —CN,        -   phenyl,        -   —O-phenyl,        -   4-7 membered heterocycloalkyl comprising one to three            heteroatoms independently selected from N, O, and S, or        -   5-6 membered heteroaryl comprising one to three heteroatoms            independently selected from N, O, and S; optionally            substituted with one or more independently selected C₁₋₄            alkyl, C₁₋₄ alkoxy, CN, halo, and —C(═O)OR¹¹;    -   R⁷ is C₁₋₄ alkyl, or halo, and    -   each of R⁸, R⁹, R¹⁰ and R¹¹ is independently selected from H and        C₁₋₄ alkyl.

In a further aspect, the present invention provides pharmaceuticalcompositions comprising a compound of the invention, and apharmaceutical carrier, excipient or diluent. Moreover, a compound ofthe present invention useful in the pharmaceutical compositions andtreatment methods disclosed herein, is pharmaceutically acceptable asprepared and used. In this aspect of the invention, the pharmaceuticalcomposition may additionally comprise further active ingredientssuitable for use in combination with a compound of the invention.

In another aspect of the invention, this invention provides novelcompounds of the invention for use in therapy.

In a further aspect of the invention, this invention provides a methodof treating a mammal susceptible to or afflicted with a condition fromamong those listed herein, and particularly, such condition as may beassociated with aberrant activity of GPR84 and/or aberrant GPR84expression and/or aberrant GPR84 distribution, for example inflammatoryconditions (for example inflammatory bowel diseases (IBD), rheumatoidarthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonarydisease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonaryfibrosis (IPF))), neuroinflammatory conditions, infectious diseases,autoimmune diseases, endocrine and/or metabolic diseases, and/ordiseases involving impairment of immune cell functions, which methodcomprises administering a therapeutically effective amount of a compoundof the invention, or one or more of the pharmaceutical compositionsherein described.

In a further aspect, the present invention provides a compound of theinvention for use in the treatment or prevention of a condition selectedfrom those listed herein, particularly such conditions as may beassociated with aberrant activity of GPR84 and/or aberrant GPR84expression and/or aberrant GPR84 distribution expression such asinflammatory conditions (for example inflammatory bowel diseases (IBD),rheumatoid arthritis, vasculitis, lung diseases (e.g. chronicobstructive pulmonary disease (COPD) and lung interstitial diseases(e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatoryconditions, infectious diseases, autoimmune diseases, endocrine and/ormetabolic diseases, and/or diseases involving impairment of immune cellfunctions.

In additional aspects, this invention provides methods for synthesizinga compound of the invention, with representative synthetic protocols andpathways disclosed herein.

Accordingly, it is a principal object of this invention to provide acompound of the invention, which can modify the activity of GPR84 andthus prevent or treat any conditions that may be causally relatedthereto.

It is further an object of this invention to provide a compound of theinvention that can treat or alleviate conditions or diseases or symptomsof same, such as inflammatory conditions (for example inflammatory boweldiseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g.chronic obstructive pulmonary disease (COPD) and lung interstitialdiseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatoryconditions, infectious diseases, autoimmune diseases, endocrine and/ormetabolic diseases, and/or diseases involving impairment of immune cellfunctions, that may be causally related to the activity and/orexpression and/or distribution of GPR84.

A still further object of this invention is to provide pharmaceuticalcompositions that may be used in the treatment or prevention of avariety of disease states, including the diseases associated withaberrant activity of GPR84 and/or aberrant GPR84 expression and/oraberrant GPR84 distribution such as inflammatory conditions (for exampleinflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis,lung diseases (e.g. chronic obstructive pulmonary disease (COPD) andlung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))),neuroinflammatory conditions, infectious diseases, autoimmune diseases,endocrine and/or metabolic diseases, and/or diseases involvingimpairment of immune cell functions.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention.

When describing the invention, which may include compounds,pharmaceutical compositions containing such compounds and methods ofusing such compounds and compositions, the following terms, if present,have the following meanings unless otherwise indicated. It should alsobe understood that when described herein any of the moieties definedforth below may be substituted with a variety of substituents, and thatthe respective definitions are intended to include such substitutedmoieties within their scope as set out below. Unless otherwise stated,the term ‘substituted’ is to be defined as set out below. It should befurther understood that the terms ‘groups’ and ‘radicals’ can beconsidered interchangeable when used herein.

The articles ‘a’ and ‘an’ may be used herein to refer to one or to morethan one (i.e. at least one) of the grammatical objects of the article.By way of example ‘an analogue’ means one analogue or more than oneanalogue.

‘Alkyl’ means straight or branched aliphatic hydrocarbon having thespecified number of carbon atoms. Particular alkyl groups have 1 to 6carbon atoms or 1 to 4 carbon atoms. Branched means that one or morealkyl groups such as methyl, ethyl or propyl is attached to a linearalkyl chain. Particular alkyl groups are methyl, ethyl, n-propyl,isopropyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, and1,2-dimethylbutyl. Particular alkyl groups have between 1 and 4 carbonatoms.

‘Alkylene’ refers to divalent alkane radical groups having the number ofcarbon atoms specified, in particular 1 to 6 carbon atoms and moreparticularly 1 to 4 carbon atoms which can be straight-chained orbranched. This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂—CH₂—), the propylene isomers (e.g., —CH₂—CH₂—CH₂— and—CH(CH₃)—CH₂—) and the like.

‘Alkenylene’ refers to divalent alkene radical groups having the numberof carbon atoms and the number of double bonds specified, in particular2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which canbe straight-chained or branched. This term is exemplified by groups suchas —CH═CH—, —CH₂—CH═CH—, —C(CH₃)═CH—, —C(CH₃)═CH—CH₂—, —C(CH₃)═C(CH₃)—,and —CH₂—C(CH₃)═CH—.

‘Alkynylene’ refers to divalent alkyne radical groups having the numberof carbon atoms and the number of triple bonds specified, in particular2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which canbe straight-chained or branched. This term is exemplified by groups suchas —C≡C—, —CH₂—C≡C—, and —C(CH₃)H—C≡CH—.

‘Alkoxy’ refers to the group O-alkyl, where the alkyl group has thenumber of carbon atoms specified. In particular the term refers to thegroup —O—C₁-C₆ alkyl. Particular alkoxy groups are methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are loweralkoxy, i.e. with between 1 and 6 carbon atoms. Further particularalkoxy groups have between 1 and 4 carbon atoms.

‘Amino’ refers to the radical —NH₂.

‘Aryl’ refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. In particular aryl refers to an aromatic ringstructure, mono-cyclic or poly-cyclic that includes the number of ringmembers specified. Particular aryl groups have from 6 to 10 ringmembers. Where the aryl group is a monocyclic ring system itpreferentially contains 6 carbon atoms. Particularly aryl groups includephenyl, naphthyl, indenyl, and tetrahydronaphthyl.

‘Carboxy’ refers to the radical —C(O)OH.

‘Cycloalkyl’ refers to cyclic non-aromatic hydrocarbyl groups having thenumber of carbon atoms specified. Particular cycloalkyl groups have from3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example,single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl.

‘Cyano’ refers to the radical —CN.

‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) andiodo (I). Particular halo groups are either fluoro or chloro.

‘Hetero’ when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g.heteroaryl, and the like having from 1 to 5, and particularly from 1 to3 heteroatoms.

‘Heteroaryl’ means an aromatic ring structure, mono-cyclic orpolycyclic, that includes one or more heteroatoms and the number of ringmembers specified. Particular heteraryl groups have 5 to 10 ringmembers, or 5 to 6 ring members. The heteroaryl group can be, forexample, a five membered or six membered monocyclic ring or a bicyclicstructure formed from fused five and six membered rings or two fused sixmembered rings or, by way of a further example, two fused five memberedrings. Each ring may contain up to four heteroatoms typically selectedfrom nitrogen, sulphur and oxygen. Typically the heteroaryl ring willcontain up to 4 heteroatoms, more typically up to 3 heteroatoms, moreusually up to 2, for example a single heteroatom. In one embodiment, theheteroaryl ring contains at least one ring nitrogen atom. The nitrogenatoms in the heteroaryl rings can be basic, as in the case of animidazole or pyridine, or essentially non-basic as in the case of anindole or pyrrole nitrogen. In general the number of basic nitrogenatoms present in the heteroaryl group, including any amino groupsubstituents of the ring, will be less than five. Examples of fivemembered monocyclic heteroaryl groups include but are not limited topyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole,oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole andtetrazole groups. Examples of six membered monocyclic heteroaryl groupsinclude but are not limited to pyridine, pyrazine, pyridazine,pyrimidine and triazine. Particular examples of bicyclic heteroarylgroups containing a five membered ring fused to another five memberedring include but are not limited to imidazothiazole andimidazoimidazole. Particular examples of bicyclic heteroaryl groupscontaining a six membered ring fused to a five membered ring include butare not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole,isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole,isobenzofuran, indole, isoindole, isoindolone, indolizine, indoline,isoindoline, purine (e.g., adenine, guanine), indazole,pyrazolopyrimidine, triazolopyrimidine, benzodioxole andpyrazolopyridine groups. Particular examples of bicyclic heteroarylgroups containing two fused six membered rings include but are notlimited to quinoline, isoquinoline, chroman, thiochroman, chromene,isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine,benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline,phthalazine, naphthyridine and pteridine groups. Particular heteroarylgroups are those derived from thiophene, pyrrole, benzothiophene,benzofuran, indole, pyridine, quinoline, imidazole, oxazole andpyrazine.

Examples of representative heteroaryls include the following:

wherein each Y is selected from >C═O, NH, O and S.

As used herein, the term ‘heterocycloalkyl’ refers to a stableheterocyclic non-aromatic ring and/or rings containing one or moreheteroatoms independently selected from N, O and S, fused theretowherein the group contains the number of ring members specified.Particular heterocycloalkyl groups have 4-10 ring members or 5 to 7 ringmembers, or 5 to 6 ring members. The heterocycloalkyl group can be, forexample, a five membered or six membered monocyclic ring or a bicyclicstructure formed from fused five and six membered rings or two fused sixmembered rings or, by way of a further example, two fused five memberedrings. Each ring may contain up to four heteroatoms typically selectedfrom nitrogen, sulphur and oxygen. Typically the heterocycloalkyl ringwill contain up to 4 heteroatoms, more typically up to 3 heteroatoms,more usually up to 2, for example a single heteroatom. In oneembodiment, the heterocycloalkyl ring contains at least one ringnitrogen atom. A fused heterocyclic ring system may include carbocyclicrings and need only include one heterocyclic ring. Examples ofheterocyclic rings include, but are not limited to, morpholine,piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and4-piperidinyl), pyrrolidine (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran),dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole,tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g.4-tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline,thiazoline, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methyl piperazine. Further examples includethiomorpholine and its S-oxide and S,S-dioxide (particularlythiomorpholine). Still further examples include azetidine, piperidone,piperazone, and N-alkyl piperidines such as N-methyl piperidine.Particular examples of heterocycloalkyl groups are shown in thefollowing illustrative examples:

wherein each W is selected from CH₂, NH, O and S; and each Y is selectedfrom NH, O, CO, SO₂, and S.

‘Hydroxy’ refers to the radical —OH.

‘Nitro’ refers to the radical —NO₂.

‘Substituted’ refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituent(s).

‘Thiol’ refers to the group —SH.

‘Thioalkoxy’ refers to the group —SR¹⁰ where R¹⁰ is an alkyl group withthe number of carbon atoms specified. In particular thioalkoxy groupswhere R¹⁰ is a C₁-C₆ alkyl. Particular thioalkoxy groups arethiomethoxy, thioethoxy, n-thiopropoxy, thioisopropoxy, n-thiobutoxy,tert-thiobutoxy, sec-thiobutoxy, n-thiopentoxy, n-thiohexoxy, and1,2-dimethylthiobutoxy. Particular thioalkoxy groups are lowerthioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particularthioalkoxy groups have between 1 and 4 carbon atoms.

As used herein, the term ‘substituted with one or more’ refers to one tofour substituents. In one embodiment it refers to one to threesubstituents. In further embodiments it refers to one or twosubstituents. In a yet further embodiment it refers to one substituent.

One having ordinary skill in the art of organic synthesis will recognizethat the maximum number of heteroatoms in a stable, chemically feasibleheterocyclic ring, whether it is aromatic or non aromatic, is determinedby the size of the ring, the degree of unsaturation and the valence ofthe heteroatoms. In general, a heterocyclic ring may have one to fourheteroatoms so long as the heteroaromatic ring is chemically feasibleand stable.

‘Pharmaceutically acceptable’ means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

‘Pharmaceutically acceptable salt’ refers to a salt of a compound thatis pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. In particular, suchsalts are non-toxic may be inorganic or organic acid addition salts andbase addition salts. Specifically, such salts include: (1) acid additionsalts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. The term‘pharmaceutically acceptable cation’ refers to an acceptable cationiccounter-ion of an acidic functional group. Such cations are exemplifiedby sodium, potassium, calcium, magnesium, ammonium, tetraalkylammoniumcations, and the like.

‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered.

‘Prodrugs’ refers to compounds, including derivatives of the compoundsof the invention, which have cleavable groups and become by solvolysisor under physiological conditions the compounds of the invention whichare pharmaceutically active in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like.

‘Solvate’ refers to forms of the compound that are associated with asolvent, usually by a solvolysis reaction. This physical associationincludes hydrogen bonding. Conventional solvents include water, ethanol,acetic acid and the like. The compounds of the invention may be preparede.g. in crystalline form and may be solvated or hydrated. Suitablesolvates include pharmaceutically acceptable solvates, such as hydrates,and further include both stoichiometric solvates and non-stoichiometricsolvates. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. ‘Solvate’ encompasses bothsolution-phase and isolable solvates. Representative solvates includehydrates, ethanolates and methanolates.

‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’are used interchangeably herein.

‘Effective amount’ means the amount of a compound of the invention that,when administered to a subject for treating a disease, is sufficient toeffect such treatment for the disease. The “effective amount” can varydepending on the compound, the disease and its severity, and the age,weight, etc., of the subject to be treated.

‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiringor developing a disease or disorder (i.e., causing at least one of theclinical symptoms of the disease not to develop in a subject that may beexposed to a disease-causing agent, or predisposed to the disease inadvance of disease onset.

The term ‘prophylaxis’ is related to ‘prevention’, and refers to ameasure or procedure the purpose of which is to prevent, rather than totreat or cure a disease. Non-limiting examples of prophylactic measuresmay include the administration of vaccines; the administration of lowmolecular weight heparin to hospital patients at risk for thrombosisdue, for example, to immobilization; and the administration of ananti-malarial agent such as chloroquine, in advance of a visit to ageographical region where malaria is endemic or the risk of contractingmalaria is high.

‘Treating’ or ‘treatment’ of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting thedisease or reducing the manifestation, extent or severity of at leastone of the clinical symptoms thereof). In another embodiment ‘treating’or ‘treatment’ refers to ameliorating at least one physical parameter,which may not be discernible by the subject. In yet another embodiment,‘treating’ or ‘treatment’ refers to modulating the disease or disorder,either physically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In a further embodiment, “treating” or “treatment” relates to slowingthe progression of the disease.

As used herein the term ‘inflammatory condition(s)’ refers to the groupof conditions including, rheumatoid arthritis, osteoarthritis, juvenileidiopathic arthritis, vasculitis, psoriasis, gout, allergic airwaydisease (e.g. asthma, rhinitis), inflammatory bowel diseases (e.g.Crohn's disease, ulcerative colitis), and endotoxin-driven diseasestates (e.g. complications after bypass surgery or chronic endotoxinstates contributing to e.g. chronic cardiac failure). Particularly theterm refers to rheumatoid arthritis, allergic airway disease (e.g.asthma) and inflammatory bowel diseases.

As used herein, the term ‘infectious diseases’ refers to bacterialinfectious diseases and includes but is not limited to conditions suchas sepsis, septicemia, endotoxemia, systemic inflammatory responsesyndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, andother infections involving, for example, Yersinia, Salmonella,Chlamydia, Shigella, or enterobacteria species.

As used herein the term ‘autoimmune disease(s)’ refers to the group ofdiseases including obstructive airways disease (including conditionssuch as COPD (Chronic obstructive pulmonary disease)), psoriasis, asthma(e.g intrinsic asthma, extrinsic asthma, dust asthma, infantily asthma)particularly chronic or inveterate asthma (for example late asthma andairway hyperreponsiveness), bronchitis, including bronchial asthma,systemic lupus erythematosus (SLE), multiple sclerosis, type I diabetesmellitus and complications associated therewith, atopic eczema (atopicdermatitis), contact dermatitis and further eczematous dermatitis,vasculitis, inflammatory bowel disease (e.g. Crohn's disease andulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis.Particularly the term refers to COPD, asthma, psoriasis, systemic lupuserythematosis, type I diabetes mellitus, vasculitis and inflammatorybowel disease.

As used herein the term ‘endocrine and/or metabolic disease(s)’ refersto the group of conditions involving the body's over- orunder-production of certain hormones, while metabolic disorders affectthe body's ability to process certain nutrients and vitamins. Endocrinedisorders include hypothyroidism, congenital adrenal hyperplasia,diseases of the parathyroid gland, diabetes mellitus, diseases of theadrenal glands (including Cushing's syndrome and Addison's disease), andovarian dysfunction (including polycystic ovary syndrome), among others.Some examples of metabolic disorders include cystic fibrosis,phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

As used herein, the term ‘diseases involving impairment of immune cellfunctions’ includes conditions with symptoms such as recurrent and drawnout viral and bacterial infections, and slow recovery. Other invisiblesymptoms may be the inability to kill off parasites, yeasts andbacterial pathogens in the intestines or throughout the body.

As used herein the term ‘neuroinflammatory conditions’ refers todiseases or disorders characterized by abrupt neurologic deficitsassociated with inflammation, demyelination, and axonal damage, andincludes but is not limited to conditions such as Guillain-Barrésyndrome (GBS), multiple sclerosis, axonal degeneration, autoimmuneencephalomyelitis.

‘Compound(s) of the invention’, and equivalent expressions, are meant toembrace compounds of the Formula (e) as herein described, whichexpression includes the pharmaceutically acceptable salts, and thesolvates, e.g., hydrates, and the solvates of the pharmaceuticallyacceptable salts where the context so permits. Similarly, reference tointermediates, whether or not they themselves are claimed, is meant toembrace their salts, and solvates, where the context so permits.

When ranges are referred to herein, for example but without limitation,C₁₋₆ alkyl, the citation of a range should be considered arepresentation of each member of said range.

Other derivatives of the compounds of this invention have activity inboth their acid and acid derivative forms, but in the acid sensitiveform often offers advantages of solubility, tissue compatibility, ordelayed release in the mammalian organism (see, Bundgard, H., Design ofProdrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs includeacid derivatives well know to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acid with a suitablealcohol, or amides prepared by reaction of the parent acid compound witha substituted or unsubstituted amine, or acid anhydrides, or mixedanhydrides. Simple aliphatic or aromatic esters, amides and anhydridesderived from acidic groups pendant on the compounds of this inventionare particularly useful prodrugs. In some cases it is desirable toprepare double ester type prodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the C₁ toC₈ alkyl, and substituted or unsubstituted C₆₋₁₀ aryl, esters of thecompounds of the invention.

As used herein, the term ‘isotopic variant’ refers to a compound thatcontains unnatural proportions of isotopes at one or more of the atomsthat constitute such compound For example, an ‘isotopic variant’ of acompound can contain one or more non-radioactive isotopes, such as forexample, deuterium (²H or D), carbon-13 (¹³C), nitrogen-15 (¹⁵N), or thelike. It will be understood that, in a compound where such isotopicsubstitution is made, the following atoms, where present, may vary, sothat for example, any hydrogen may be ²H/D, any carbon may be ¹³C, orany nitrogen may be ¹⁵N, and that the presence and placement of suchatoms may be determined within the skill of the art. Likewise, theinvention may include the preparation of isotopic variants withradioisotopes, in the instance for example, where the resultingcompounds may be used for drug and/or substrate tissue distributionstudies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e.¹⁴C, are particularly useful for this purpose in view of their ease ofincorporation and ready means of detection. Further, compounds may beprepared that are substituted with positron emitting isotopes, such as¹¹C, ¹⁸F, ¹⁵O and ¹³N, and would be useful in Positron EmissionTopography (PET) studies for examining substrate receptor occupancy.

All isotopic variants of the compounds provided herein, radioactive ornot, are intended to be encompassed within the scope of the invention.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed ‘isomers’. Isomersthat differ in the arrangement of their atoms in space are termed‘stereoisomers’.

Stereoisomers that are not mirror images of one another are termed‘diastereomers’ and those that are non-superimposable mirror images ofeach other are termed ‘enantiomers’. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a ‘racemic mixture’.

‘Tautomers’ refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

The compounds of the invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

It will be appreciated that compounds of the invention may bemetabolized to yield biologically active metabolites.

THE COMPOUNDS

The present invention relates to novel compounds that antagonize GPR84and that may be useful for the treatment of inflammatory conditions (forexample inflammatory bowel diseases (IBD), rheumatoid arthritis,vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease(COPD) and lung interstitial diseases (e.g. idiopathic pulmonaryfibrosis (IPF))), neuroinflammatory conditions, infectious diseases,autoimmune diseases, endocrine and/or metabolic diseases, and/ordiseases involving impairment of immune cell functions.

The present invention also provides methods for the production of thecompounds of the invention, pharmaceutical compositions comprising thecompounds of the invention and methods for treating diseases involvinginflammatory conditions (for example inflammatory conditions (forexample inflammatory bowel diseases (IBD), rheumatoid arthritis,vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease(COPD) and lung interstitial diseases (e.g. idiopathic pulmonaryfibrosis (IPF))), neuroinflammatory conditions, infectious diseases,autoimmune diseases, endocrine and/or metabolic diseases, and/ordiseases involving impairment of immune cell functions, by administeringa compound of the invention. A compound of the invention is an inhibitorof GPR84.

Accordingly, in a first aspect of the invention, a compound of theinvention is disclosed having a Formula Ia:

-   -   wherein    -   R¹ is H, Me, or halo;    -   L₁ is absent or is —O—, —S—, or —NR^(4a)—;    -   G is        -   R²,        -   —W-L₂-R², or        -   —W-L₃-R³    -   W is C₁₋₄ alkylene, C₂₋₄ alkenylene having one double bond, or        C₂₋₄ alkynylene having one triple bond;    -   L₂ is absent or is —O—;    -   R² is        -   H,        -   C₁₋₈ alkyl, optionally substituted with one to three groups            independently selected from            -   OH,            -   halo,            -   CN,            -   C₁₋₆ alkoxy,            -   C₃₋₇ cycloalkyl,            -   4-6 membered heterocycloalkyl comprising one to three                heteroatoms independently selected from S, and O,            -   5-6 membered heteroaryl comprising one to three                heteroatoms independently selected from N, S, and O, and            -   phenyl,        -   C₄₋₇ cycloalkenyl comprising one double bond,        -   5-7 membered heterocycloalkenyl comprising one double bond,            and one to three heteroatoms independently selected from N,            O, and S,        -   C₃₋₇ cycloalkyl optionally substituted with one or more            independently selected R⁵ groups,        -   4-10 membered heterocycloalkyl comprising one to two            heteroatoms independently selected from S, and O, optionally            substituted with one to three independently selected R⁵            groups,        -   5-10 membered heteroaryl comprising one to three heteroatoms            independently selected from N, S, and O, optionally            substituted with one to three independently selected R⁶            groups, or        -   C₆₋₁₀ aryl optionally substituted with one or more            independently selected R⁶ groups;    -   L₃ is —NR^(4b)—;    -   R³ is        -   —C₁₋₄ alkyl substituted with            -   C₆₋₁₀ aryl optionally substituted with one or more                independently selected R⁷ groups, or            -   5-10 membered heteroaryl comprising one to three                heteroatoms independently selected from N, S, and O,                optionally substituted with one or more R independently                selected R⁷ groups,        -   5-10 membered heteroaryl comprising one to three heteroatoms            independently selected from N, S, and O, optionally            substituted with one or more independently selected R⁷            groups, or        -   C₆₋₁₀ aryl optionally substituted with one or more            independently selected R⁷ groups;    -   Each R^(4a) and R^(4b) is independently selected from H, C₁₋₄        alkyl, and C₃₋₇ cycloalkyl;    -   R⁵ is oxo or R⁶;    -   R⁶ is        -   —OH,        -   halo,        -   —NO₂,        -   C₁₋₆ alkyl optionally substituted with one to three groups            independently selected from halo, and OH,        -   C₁₋₆ alkoxy optionally substituted with one to three groups            independently selected from halo, and OH,        -   C₃₋₇ cycloalkyl,        -   —C(═O)OR⁸,        -   —C(═O)NR⁹R¹⁰,        -   —NHC(═O)—C₁₋₄ alkyl,        -   —CN,        -   phenyl,        -   —O-phenyl,        -   4-7 membered heterocycloalkyl comprising one to three            heteroatoms independently selected from N, O, and S, or        -   5-6 membered heteroaryl comprising one to three heteroatoms            independently selected from N, O, and S; optionally            substituted with one or more independently selected C₁₋₄            alkyl, C₁₋₄ alkoxy, CN, halo, and —C(═O)OR¹¹;    -   R⁷ is C₁₋₄ alkyl, or halo; and    -   each of R⁸, R⁹, R¹⁰ and R¹¹ is independently selected from H and        C₁₋₄ alkyl.

In a further embodiment, a compound of the invention is disclosed havinga Formula Ib:

wherein R¹, L₁ and G are as previously described.

In yet a further embodiment, a compound of the invention is disclosedhaving a Formula Ic:

wherein R¹, L₁ and G are as previously described.

In one embodiment, the compound of the invention is according to FormulaIa, Ib or Ic, wherein R¹ is Me, F, or Cl.

In one embodiment, the compound of the invention is according to FormulaIa, Ib or Ic, wherein R¹ is H.

In one embodiment, the compound of the invention is according to FormulaIIa, IIb, or IIc:

wherein L₁, and R² are as described previously.

In one embodiment, the compound of the invention is according to FormulaIIIa, IIIb, or IIIc:

wherein L₁, W, L₂, and R² are as described previously.

In one embodiment, the compound of the invention is according to FormulaIVa, IVb, or IVc:

wherein L₁, W, L₃, and R³ are as described previously.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-IVc, wherein L₁ is absent, or is —O—. In a preferredembodiment, L₁ is absent.

In another embodiment, the compound of the invention is according to anyone of Formulae Ia-IVc, wherein L₁ is —NR^(4a)—, wherein R^(4a) is asdescribed previously. In a preferred embodiment, R^(4a) is H, Me, Et, orcyclopropyl. In a more preferred embodiment, R^(4a) is H.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-Ic, or IIIa-IVc, wherein W is C₁₋₄ alkylene. In apreferred embodiment, W is —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH(CH₃)—,—CH₂—CH(—CH₂—CH₃)—, —CH₂—C(CH₃)₂—, or —CH₂—CH₂—CH₂—. In a more preferredembodiment, W is —CH₂—. In another more preferred embodiment, W is—CH₂—CH₂—.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-Ic, or IIIa-IVc, wherein W is C₂₋₄ alkenylene having onedouble bond. In a preferred embodiment, W is —CH═CH—, —CH₂—CH═CH—, or—CH═CH—CH₂—. In a more preferred embodiment, W is —CH═CH—. In anothermore preferred embodiment, W is —CH₂—CH═CH—.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-Ic, or IIIa-IVc, wherein W is C₂₋₄ alkynylene having onetriple bond. In a preferred embodiment, W is —C≡C—, —CH₂—C≡C—, or—C≡C—CH₂—. In a more preferred embodiment, W is —C≡C—. In another morepreferred embodiment, W is —CH₂—C≡C—.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-Ic, or IIIa-IIIc, wherein L₂ is absent. In anotherembodiment, L₂ is —O—.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-Ic, or IIIa-IIIc, wherein L₁ is absent or is —O—, W isC₁₋₄ alkylene; and L₂ and R² are as described previously. In a preferredembodiment, W is —CH₂—, —CH₂—CH₂—, or —CH₂—CH₂—CH₂—. In a more preferredembodiment, W is —CH₂—. In another preferred embodiment, W is —CH₂—CH₂—.

In another embodiment, the compound of the invention is according to anyone of Formulae Ia-Ic, or IIIa-IIIc, wherein L₁ is absent or is —O—, Wis C₂₋₄ alkenylene having one double bond; and L₂ and R² are asdescribed previously. In a preferred embodiment, W is —CH═CH—,—CH₂—CH═CH—, or —CH═CH—CH₂—. In a more preferred embodiment, W is—CH═CH—. In another more preferred embodiment, W is —CH₂—CH═CH—.

In yet another embodiment, the compound of the invention is according toany one of Formulae Ia-Ic, or IIIa-IIIc, wherein L₁ is absent, W is C₂₋₄alkynylene having one triple bond; and L₂ and R² are as describedpreviously. In a preferred embodiment, W is —C≡C—, —CH₂—C≡C—, or—C≡C—CH₂—. In a more preferred embodiment, W is —C≡C—. In another morepreferred embodiment, W is —CH₂—C≡C—.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-Ic, or IIIa-IIIc, wherein L₁ and L₂ are absent, W is C₁₋₄alkylene; and R² is as described previously. In a preferred embodiment,W is —CH₂—, —CH₂—CH₂—, or —CH₂—CH₂—CH₂—. In a more preferred embodiment,W is —CH₂—. In another more preferred embodiment, W is —CH₂—CH₂—.

In another embodiment, the compound of the invention is according to anyone of Formulae Ia-Ic, or IIIa-IIIc, wherein L₁ and L₂ are absent, W isC₂₋₄ alkenylene having one double bond; and R² is as describedpreviously. In a preferred embodiment, W is —CH═CH—, —CH₂—CH═CH—, or—CH═CH—CH₂—. In a more preferred embodiment, W is —CH═CH—. In anothermore preferred embodiment, W is —CH₂—CH═CH—.

In yet another embodiment, the compound of the invention is according toany one of Formulae Ia-Ic, or IIIa-IIIc, wherein L₁ and L₂ are absent, Wis C₂₋₄ alkynylene having one triple bond; and R² is as describedpreviously. In a preferred embodiment, W is —C≡C—, —CH₂—C≡C—, or—C≡C—CH₂—. In a more preferred embodiment, W is —C≡C—. In another morepreferred embodiment, W is —CH₂—C≡C—.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-IIIc, wherein R² is H.

In another embodiment, the compound of the invention is according to anyone of Formulae any one of Formulae Ia-IIIc, wherein R² is C₁₋₈ alkyl.In a preferred embodiment, R² is Me, Et, n-Pr, i-Pr, i-Bu, or t-Bu. In amore preferred embodiment, R² is Me, Et, i-Pr or t-Bu. In a morepreferred embodiment, R² is t-Bu.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-IIIc, wherein R² is C₁₋₈ alkyl substituted with one tothree groups selected from OH, halo, CN, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl,4-6 membered heterocycloalkyl (comprising one to three heteroatomsindependently selected from S, and O), 5-6 membered heteroaryl(comprising one to three heteroatoms independently selected from N, S,and O), and phenyl. In a preferred embodiment, R² is Me, Et, n-Pr, i-Pr,i-Bu, or t-Bu substituted with one to three groups selected from OH,halo, CN, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, 4-6 membered heterocycloalkyl(comprising one to three heteroatoms independently selected from S, andO), 5-6 membered heteroaryl (comprising one to three heteroatomsindependently selected from N, S, and O), and phenyl. In anotherpreferred embodiment, is C₁₋₈ alkyl substituted with one to three groupsselected from OH, F, Cl, CN, —OMe, —OEt, Oi-Pr, cyclopropyl, cyclobutyl,oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl,triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, andphenyl. In a more preferred embodiment, R² is Me, Et, n-Pr, i-Pr, i-Bu,or t-Bu substituted with one to three groups selected from OH, F, Cl,CN, —OMe, —OEt, —Oi-Pr, cyclopropyl, cyclobutyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl,oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and phenyl.

In another embodiment, the compound of the invention is according to anyone of Formulae Ia-IIIc, wherein R² is C₁₋₈ alkyl substituted with onegroup selected from OH, halo, CN, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, 4-6membered heterocycloalkyl (comprising one to three heteroatomsindependently selected from S, and O), 5-6 membered heteroaryl(comprising one to three heteroatoms independently selected from N, S,and O), and phenyl. In a preferred embodiment, R² is Me, Et, n-Pr, i-Pr,i-Bu, or t-Bu substituted with one group selected from OH, halo, CN,C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, 4-6 membered heterocycloalkyl (comprisingone to three heteroatoms independently selected from S, and O), 5-6membered heteroaryl (comprising one to three heteroatoms independentlyselected from N, S, and O), and phenyl. In another preferred embodiment,is C₁₋₈ alkyl substituted with one group selected from OH, F, Cl, CN,—OMe, —OEt, —Oi-Pr, cyclopropyl, cyclobutyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl,oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl. In amore preferred embodiment, R² is Me, Et, n-Pr, i-Pr, i-Bu, or t-Busubstituted with one group selected from OH, F, Cl, CN, —OMe, —OEt,—Oi-Pr, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl,oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl. In amost preferred embodiment, R² is —CH₂—OH, —C(CH₃)₂—OH, —CH(OH)CH₃,—CH(OH)—C₂H₅, —CH(OH)—C₃H₇, —C(OH)(C₂H₅)₂, —C(OH)H—CH(CH₃)₂,—C(OH)H—CH₂—CH(CH₃)₂, —C(OH)H—C(CH₃)₃, —CH₂—CN, —CH₂—OCH₃,—CH₂—CH₂—OCH₃, —CH(OCH₃)—CH₃, —C(OCH₃)H—CH(CH₃)₂, —CH₂—F, —CH₂—CH₂—F,—CH₂-cyclopropyl, —CH₂-cyclopentyl, —CH₂-oxetanyl,—CH₂-tetrahydrofuranyl, or —CH₂-tetrahydropyranyl.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-IIIc, wherein R² is C₄₋₇ cycloalkenyl comprising onedouble bond. In a preferred embodiment, R² is cyclohexenyl.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-IIIc, wherein R² is 5-7 membered heterocycloalkenylcomprising one double bond, and one to three heteroatoms independentlyselected from N, O, and S. In a preferred embodiment, R² isdihydropyranyl.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-IIIc, wherein R² is C₃₋₇ cycloalkyl. In a preferredembodiment, R² is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.In a more preferred embodiment, R² is cyclopropyl.

In another embodiment, the compound of the invention is according to anyone of Formulae Ia-IIIc, wherein R² is C₃₋₇ cycloalkyl substituted withone to three independently selected R⁵ groups. In a preferredembodiment, R² is C₃₋₇ cycloalkyl substituted with one R⁵ group. In amore preferred embodiment, R² is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, each of which is substituted with one R⁵ group. In anothermore preferred embodiment, R² is C₃₋₇ cycloalkyl substituted with one R⁵group, wherein R⁵ is oxo, or R⁶ wherein R⁶ is selected from OH, or C₁₋₆alkyl. In a most preferred embodiment, R² is cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, each of which is substituted with one R⁵group, wherein R⁵ is oxo, or R⁶ wherein R⁶ is selected from OH, or C₁₋₆alkyl. In a further most preferred embodiment, R² is cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted withone R⁵ group, wherein R⁵ is R⁶, and R⁶ is selected from OH.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-IIIc, wherein R² is 4-10 membered heterocycloalkylcomprising one to two heteroatoms independently selected from S, and O.In a preferred embodiment, R² is oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, or dioxanyl.

In another embodiment, the compound of the invention is according to anyone of Formulae Ia-IIIc, R² is 4-10 membered heterocycloalkyl comprisingone to two heteroatoms independently selected from S, and O substitutedwith one to three independently selected R⁵ groups. In a preferredembodiment, R² is 4-10 membered heterocycloalkyl comprising one to twoheteroatoms independently selected from S, and Osubstituted with one R⁵group. In a more preferred embodiment, R² is 4-10 memberedheterocycloalkyl comprising one to two heteroatoms independentlyselected from S, and O substituted with one R⁵ group, wherein R⁵ isselected from oxo, or R⁶ wherein R⁶ is selected from OH, and C₁₋₆ alkyl.In another more preferred embodiment, R² is oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, or dioxanyl, each of which is substituted with one R⁵group. In a most preferred embodiment, R² is oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, each of which issubstituted with one R⁵ group, wherein R⁵ is selected from oxo, or R⁶wherein R⁶ is selected from OH, and C₁₋₆ alkyl,

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-IIIc, R² is 5-10 membered heteroaryl comprising one tothree heteroatoms independently selected from N, S, and O. In apreferred embodiment, R² is furanyl, thienyl, oxazolyl, thiazolyl,oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl,pyrimidinyl, indanyl, or indazolyl.

In another embodiment, the compound of the invention is according to anyone of Formulae Ia-IIIc, R² is 5-10 membered heteroaryl comprising oneto three heteroatoms independently selected from N, S, and O,substituted substituted with one to three independently selected R⁶groups. In a preferred embodiment, R² is 5-10 membered heteroarylcomprising one to three heteroatoms independently selected from N, S,and O, substituted substituted with one or two independently selected R⁶groups. In a more preferred embodiment, R² is furanyl, thienyl,oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl,pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, substitutedwith one or two independently selected R⁶ groups. In another morepreferred embodiment, R² is 5-10 membered heteroaryl comprising one tothree heteroatoms independently selected from N, S, and O, substitutedwith one or two independently selected R⁶ groups, wherein each R⁶ isindependently selected from OH, halo, C₁₋₆ alkyl, C₁₋₆ alkyl substitutedwith one or more halo, C₁₋₆ alkoxy, —CN, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl comprising one to three heteroatoms independentlyselected from N, O, and S, and phenyl. In most preferred embodiment, R²is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, orindazolyl, each of which is substituted with one or two independentlyselected R⁶ groups, wherein each R⁶ is independently selected from OH,halo, C₁₋₆ alkyl, C₁₋₆ alkyl substituted with one or more halo, C₁₋₆alkoxy, —CN, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl comprisingone to three heteroatoms independently selected from N, O, and S, andphenyl. In another most preferred embodiment, R² is 5-10 memberedheteroaryl comprising one to three heteroatoms independently selectedfrom N, S, and O, substituted with one or two independently selected R⁶groups, wherein each R⁶ is independently selected from OH, F, Cl, Me,Et, Pr, i-Pr, t-Bu, —CF₃, —OMe, —OEt, Oi-Pr, —CN, cyclopropyl,pyrrolidinyl, morpholinyl, piperidinyl, or phenyl. In further mostpreferred embodiment, R² is furanyl, thienyl, oxazolyl, thiazolyl,oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl,pyrimidinyl, indanyl, or indazolyl, each of which is substituted withone or two independently selected R⁶ groups, wherein each R⁶ isindependently selected from OH, F, Cl, Me, Et, Pr, i-Pr, t-Bu, —CF₃,—OMe, —OEt, —Oi-Pr, —CN, cyclopropyl, pyrrolidinyl, morpholinyl,piperidinyl, and phenyl.

In another embodiment, the compound of the invention is according to anyone of Formulae Ia-IIIc, R² is C₆₋₁₀ aryl. In a preferred embodiment, R²is phenyl.

In another embodiment, the compound of the invention is according to anyone of Formulae Ia-IIIc, R² is C₆₋₁₀ aryl substituted with one or moreindependently selected R⁶ groups. In a preferred embodiment, R² is C₆₋₁₀aryl substituted with one or two independently selected R⁶ groups. In amore preferred embodiment, R² is C₆₋₁₀ aryl substituted with one or twoindependently selected R⁶ groups, wherein each R⁶ group is selected fromhalo, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, or —NHC(═O)—C₁₋₄ alkyl. In anothermore preferred embodiment, R² is C₆₋₁₀ aryl substituted with one or twoindependently selected R⁶ groups, wherein each R⁶ group is selected from—C(═O)NR⁹R¹⁰, and each R⁹ and R¹⁰ is independently selected from H andC₁₋₄ alkyl. In yet another more preferred embodiment, R² is phenylsubstituted with one or two independently selected R⁶ groups. In a mostpreferred embodiment, R² is phenyl substituted with one or twoindependently selected R⁶ groups, wherein each R⁶ group is selected fromhalo, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —NHC(═O)—C₁₋₄ alkyl. In anothermost preferred embodiment, R² is phenyl substituted with one or twoindependently selected R⁶ groups, wherein each R⁶ group is selected from—C(═O)NR⁹R¹⁰, and each R⁹ and R¹⁰ is independently selected from H andC₁₋₄ alkyl. In a further most preferred embodiment R² is phenylsubstituted with one or two independently selected R⁶ groups, whereineach R⁶ group is selected from F, Cl, CN, Me, —OMe, —OEt, and—NHC(═O)Me. In another further most preferred embodiment R² is phenylsubstituted with one or two independently selected R⁶ groups, whereineach R⁶ group is selected from —C(═O)NH₂, and —C(═O)NHMe.

In another embodiment, the compound of the invention is according to anyone of Formulae Ia-Ic, IVa, IVb or IVc, wherein L₃ is —NR^(4b)—, andR^(4b) is as described previously. In a preferred embodiment, R^(4b) isH, Me, Et, or cyclopropyl. In a more preferred embodiment, R^(4a) is H.

In another embodiment, the compound of the invention is according to anyone of Formulae Ia-Ic, IVa, IVb or IVc, wherein R³ is C₁₋₄ alkylsubstituted with C₆₋₁₀ aryl optionally substituted with one or moreindependently selected R⁷ groups, or 5-10 membered heteroaryl comprisingone to three heteroatoms independently selected from N, S, and O,optionally substituted with one or more R independently selected R⁷groups. In a preferred embodiment, R³ is Me or Et, each of which issubstituted with C₆₋₁₀ aryl optionally substituted with one or moreindependently selected R⁷ groups), or 5-10 membered heteroarylcomprising one to three heteroatoms independently selected from N, S,and O, optionally substituted with one or more R independently selectedR⁷ groups. In another preferred embodiment, R³ is C₁₋₄ alkyl substitutedwith phenyl, or pyridyl, each of which is optionally substituted withone or more independently selected R⁷ groups. In a more preferredembodiment, R³ is C₁₋₄ alkyl substituted with phenyl, or pyridyl. In amore preferred embodiment, R³ is C₁₋₄ alkyl substituted with phenyl, orpyridyl, each of which is substituted with Me, Et, F, or Cl. In a mostpreferred embodiment, R³ is Me or Et, each of which is substituted withphenyl, or pyridyl. In a more preferred embodiment, R³ is Me or Et, eachof which is substituted with phenyl, or pyridyl, each of which issubstituted with Me, Et, F, or Cl.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-Ic, IVa, IVb or IVc, wherein R³ is 5-10 memberedheteroaryl comprising one to three heteroatoms independently selectedfrom N, S, and O. In a preferred embodiment, R³ is pyridyl.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-Ic, IVa, IVb, or IVc, wherein R³ is 5-10 memberedheteroaryl comprising one to three heteroatoms independently selectedfrom N, S, and O, substituted with one or more independently selected R⁷groups, wherein each R⁷ group is as described previously. In a preferredembodiment, R³ is pyridyl, substituted with one or more independentlyselected R⁷ groups, wherein each R⁷ group is as described previously. Inanother preferred embodiment, R³ is 5-10 membered heteroaryl comprisingone to three heteroatoms independently selected from N, S, and O,substituted with one or more independently selected R⁷ groups, whereineach R⁷ group is selected from Me, Et, F, and Cl. In a more preferredembodiment, R³ is pyridyl substituted with one or more independentlyselected R⁷ groups, wherein each R⁷ group is selected from Me, Et, F,and Cl. In a most preferred embodiment, R³ is pyridyl substituted withone R⁷ group selected from Me, Et, F, and Cl.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-Ic, IVa, IVb, or IVc, wherein R³ is C₆₋₁₀ aryl. In apreferred embodiment, R³ is phenyl.

In one embodiment, the compound of the invention is according to any oneof Formulae Ia-Ic, IVa, IVb, or IVc, wherein R³ is C₆₋₁₀ arylsubstituted with one or more independently selected R⁷ groups, whereineach R⁷ group is as described previously. In a preferred embodiment, R³is phenyl, substituted with one or more independently selected R⁷groups, wherein each R⁷ group is as described previously. In anotherpreferred embodiment, R³ is C₆₋₁₀ aryl substituted with one or moreindependently selected R⁷ groups, wherein each R⁷ group is selected fromMe, Et, F, and Cl. In a more preferred embodiment, R³ is phenylsubstituted with one or more independently selected R⁷ groups, whereineach R⁷ group is selected from Me, Et, F, and Cl. In a most preferredembodiment, R³ is phenyl substituted with one R⁷ group selected from Me,Et, F, and Cl.

In one embodiment, the compound of the invention is according to FormulaVa, Vb, Vc or Vd:

wherein R² is as described previously.

In a further embodiment, the compound of the invention is not accordingto Formula Va, Vb, Vc or Vd.

In another embodiment, the compound of the invention is according toFormula VIa, VIb, VIc or VId:

wherein R² is as described previously.

In a further embodiment, the compound of the invention is not accordingto Formula VIa, VIb, VIc or VId.

In another embodiment, the compound of the invention is according toFormula VIIIa, VIIb, VIIc or VIId:

wherein R² is as described previously.

In one embodiment, the compound of the invention is according to FormulaVa, Vb, VIIa, VIIb, VIIa, or VIIb, wherein R² is C₃₋₇ cycloalkyl. In apreferred embodiment, R² is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In a more preferred embodiment, R² is cyclopropyl.

In one embodiment, the compound of the invention is according to FormulaVa, Vb, VIIa, VIIb, VIIa, or VIIb, wherein R² is not C₃₋₇ cycloalkyl. Ina preferred embodiment, R² is not cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl. In a more preferred embodiment, R² is not cyclopropyl.

In another embodiment, the compound of the invention is according toFormula Va, Vb, VIIa, VIIb, VIIa, or VIIb, wherein R² is C₃₋₇ cycloalkylsubstituted with one to three independently selected R⁵ groups. In apreferred embodiment, R² is C₃₋₇ cycloalkyl substituted with one R⁵group. In a more preferred embodiment, R² is cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, each of which is substituted with one R⁵group. In another more preferred embodiment, R² is C₃₋₇ cycloalkylsubstituted with one R⁵ group, wherein R⁵ is oxo, or R⁶ wherein R⁶ isselected from OH, or C₁₋₆ alkyl. In a most preferred embodiment, R² iscyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which issubstituted with one R⁵ group, wherein R⁵ is oxo, or R⁶ wherein R⁶ isselected from OH, and C₁₋₆ alkyl. In a further most preferredembodiment, R² is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,each of which is substituted with one R⁵ group, wherein R⁵ is OH.

In another embodiment, the compound of the invention is according toFormula Va, Vb, VIIa, VIIb, VIIa, or VIIb, wherein R² is not C₃₋₇cycloalkyl substituted with one to three independently selected R⁵groups. In a preferred embodiment, R² is not C₃₋₇ cycloalkyl substitutedwith one R⁵ group. In a more preferred embodiment, R² is notcyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which issubstituted with one R⁵ group. In another more preferred embodiment, R²is not C₃₋₇ cycloalkyl substituted with one R⁵ group, wherein R⁵ is oxo,or R⁶ wherein R⁶ is selected from OH, and C₁₋₆ alkyl. In a mostpreferred embodiment, R² is not cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, each of which is substituted with one R⁵ group, wherein R⁵is oxo, or R⁶ wherein R⁶ is selected from OH, and C₁₋₆ alkyl. In afurther most preferred embodiment, R² is not cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, each of which is substituted with one R⁵group, wherein R⁵ is OH.

In one embodiment, the compound of the invention is according to FormulaVc, Vd, VIIc, VIId, VIIc or VIId, wherein R² is 5-10 membered heteroarylcomprising one to three heteroatoms independently selected from N, S,and O. In a preferred embodiment, R² is furanyl, thienyl, oxazolyl,thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl,pyrazinyl, pyrimidinyl, indanyl, or indazolyl.

In one embodiment, the compound of the invention is according to FormulaVc, Vd, VIIc, VIId, VIIc or VIId, wherein R² is not 5-10 memberedheteroaryl comprising one to three heteroatoms independently selectedfrom N, S, and O. In a preferred embodiment, R² is not furanyl, thienyl,oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl,pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.

In another embodiment, the compound of the invention is according toFormula Vc, Vd, VIIc, VIId, VIIc or VIId, wherein R² is 5-10 memberedheteroaryl comprising one to three heteroatoms independently selectedfrom N, S, and O, substituted with one to three independently selectedR⁶ groups. In a preferred embodiment, R² is 5-10 membered heteroarylcomprising one to three heteroatoms independently selected from N, S,and O, substituted with one or two independently selected R⁶ groups. Ina more preferred embodiment, R² is furanyl, thienyl, oxazolyl,thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl,pyrazinyl, pyrimidinyl, indanyl, or indazolyl, substituted with one ortwo independently selected R⁶ groups. In another more preferredembodiment, R² is 5-10 membered heteroaryl comprising one to threeheteroatoms independently selected from N, S, and O, substituted withone or two independently selected R⁶ groups, wherein each R⁶ isindependently selected from OH, halo, C₁₋₆ alkyl, C₁₋₆ alkyl substitutedwith one or more halo, C₁₋₆ alkoxy, —CN, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl comprising one to three heteroatoms independentlyselected from N, O, and S, and phenyl. In a most preferred embodiment,R² is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, orindazolyl, each of which is substituted with one or two independentlyselected R⁶ groups, wherein each R⁶ is independently selected from OH,halo, C₁₋₆ alkyl, C₁₋₆ alkyl substituted with one or more halo, C₁₋₆alkoxy, —CN, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl comprisingone to three heteroatoms independently selected from N, O, and S, andphenyl. In another most preferred embodiment, R² is 5-10 memberedheteroaryl comprising one to three heteroatoms independently selectedfrom N, S, and O, substituted with one or two independently selected R⁶groups, wherein each R⁶ is independently selected from OH, F, Cl, Me,Et, Pr, i-Pr, t-Bu, —CF₃, —OMe, —OEt, Oi-Pr, —CN, cyclopropyl,pyrrolidinyl, morpholinyl, piperidinyl, and phenyl. In a further mostpreferred embodiment, R² is furanyl, thienyl, oxazolyl, thiazolyl,oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl,pyrimidinyl, indanyl, or indazolyl, each of which is substituted withone or two independently selected R⁶ groups, wherein each R⁶ isindependently selected from OH, F, Cl, Me, Et, Pr, i-Pr, t-Bu, —CF₃,—OMe, —OEt, —Oi-Pr, —CN, cyclopropyl, pyrrolidinyl, morpholinyl,piperidinyl, and phenyl.

In another embodiment, the compound of the invention is according toFormula Vc, Vd, VIc, VId, VIII or VIld, wherein R² is not 5-10 memberedheteroaryl comprising one to three heteroatoms independently selectedfrom N, S, and O, substituted with one to three independently selectedR⁶ groups. In a preferred embodiment, R² is not 5-10 membered heteroarylcomprising one to three heteroatoms independently selected from N, S,and O, substituted with one or two independently selected R⁶ groups. Ina more preferred embodiment, R² is not furanyl, thienyl, oxazolyl,thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl,pyrazinyl, pyrimidinyl, indanyl, or indazolyl, substituted with one ortwo independently selected R⁶ groups. In another more preferredembodiment, R² is not 5-10 membered heteroaryl comprising one to threeheteroatoms independently selected from N, S, and O, substituted withone or two independently selected R⁶ groups, wherein each R⁶ isindependently selected from OH, halo, C₁₋₆ alkyl, C₁₋₆ alkyl substitutedwith one or more halo, C₁₋₆ alkoxy, —CN, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl comprising one to three heteroatoms independentlyselected from N, O, and S, and phenyl. In a most preferred embodiment,R² is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl,thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl,indanyl, or indazolyl, each of which is substituted with one or twoindependently selected R⁶ groups, wherein each R⁶ is independentlyselected from OH, halo, C₁₋₆ alkyl, C₁₋₆ alkyl substituted with one ormore halo, C₁₋₆ alkoxy, —CN, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl comprising one to three heteroatoms independentlyselected from N, O, and S, and phenyl. In another most preferredembodiment, R² is not 5-10 membered heteroaryl comprising one to threeheteroatoms independently selected from N, S, and O, substituted withone or two independently selected R⁶ groups, wherein each R⁶ isindependently selected from OH, F, Cl, Me, Et, Pr, i-Pr, t-Bu, —CF₃,—OMe, —OEt, Oi-Pr, —CN, cyclopropyl, pyrrolidinyl, morpholinyl,piperidinyl, and phenyl. In a further most preferred embodiment, R² isnot furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, orindazolyl, each of which is substituted with one or two independentlyselected R⁶ groups, wherein each R⁶ is independently selected from OH,F, Cl, Me, Et, Pr, i-Pr, t-Bu, —CF₃, —OMe, —OEt,—Oi-Pr, —CN,cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl.

In another embodiment, the compound of the invention is according toFormula Vc, Vd, VIc, VId, VIIc or VIId, wherein R² is C₆₋₁₀ aryl. In apreferred embodiment, R² is phenyl.

In another embodiment, the compound of the invention is according toFormula Vc, Vd, VIc or VId, wherein R² is not C₆₋₁₀ aryl. In a preferredembodiment, R² is not phenyl.

In another embodiment, the compound of the invention is according toFormula Vc, Vd, VIc, VId, VIIc or VIId, wherein R² is C₆₋₁₀ arylsubstituted with one or more independently selected R⁶ groups. In apreferred embodiment, R² is C₆₋₁₀ aryl substituted with one or twoindependently selected R⁶ groups. In a more preferred embodiment, R² isC₆₋₁₀ aryl substituted with one or two independently selected R⁶ groups,wherein each R⁶ group is selected from halo, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, and —NHC(═O)—C₁₋₄ alkyl. In another more preferred embodiment,R² is C₆₋₁₀ aryl substituted with one or two independently selected R⁶groups, wherein each R⁶ group is selected from —C(═O)NR⁹R¹⁰, and each R⁹and R¹⁰ is independently selected from H and C₁₋₄ alkyl. In another morepreferred embodiment, R² is phenyl substituted with one or twoindependently selected R⁶ groups. In a most preferred embodiment, R² isphenyl substituted with one or two independently selected R⁶ groups,wherein each R⁶ group is selected from halo, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, and —NHC(═O)—C₁₋₄ alkyl. In another most preferred embodiment,R² is phenyl substituted with one or two independently selected R⁶groups, wherein each R⁶ group is selected from —C(═O)NR⁹R¹⁰, and each R⁹and R¹⁰ is independently selected from H and C₁₋₄ alkyl. In a furthermost preferred embodiment R² is phenyl substituted with one or twoindependently selected R⁶ groups, wherein each R⁶ group is selected fromF, Cl, CN, Me, —OMe, —OEt, —and —NHC(═O)Me. In a further most preferredembodiment R² is phenyl substituted with one or two independentlyselected R⁶ groups, wherein each R⁶ group is selected from C(═O)NH₂, and—C(═O)NHMe.

In another embodiment, the compound of the invention is according toFormula Vc, Vd, VIc, VId, VIIc or VIId, wherein R² is not C₆₋₁₀ arylsubstituted with one or more independently selected R⁶ groups. In apreferred embodiment, R² is not C₆₋₁₀ aryl substituted with one or twoindependently selected R⁶ groups. In a more preferred embodiment, R² isnot C₆₋₁₀ aryl substituted with one or two independently selected R⁶groups, wherein each R⁶ group is selected from halo, CN, C₁₋₆ alkyl,C₁₋₆ alkoxy, and —NHC(═O)—C₁₋₄ alkyl. In another more preferredembodiment, R² is not C₆₋₁₀ aryl substituted with one or twoindependently selected R⁶ groups, wherein each R⁶ group is selected from—C(═O)NR⁹R¹⁰, and each R⁹ and R¹⁰ is independently selected from H andC₁₋₄ alkyl. In another more preferred embodiment, R² is not phenylsubstituted with one or two independently selected R⁶ groups. In a mostpreferred embodiment, R² is not phenyl substituted with one or twoindependently selected R⁶ groups, wherein each R⁶ group is selected fromhalo, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —NHC(═O)—C₁₋₄ alkyl. In anothermost preferred embodiment, R² is not phenyl substituted with one or twoindependently selected R⁶ groups, wherein each R⁶ group is selected from—C(═O)NR⁹R¹⁰, and each R⁹ and R¹⁰ is independently selected from H andC₁₋₄ alkyl. In a further most preferred embodiment R² is not phenylsubstituted with one or two independently selected R⁶ groups, whereineach R⁶ group is selected from F, Cl, CN, Me, —OMe, —OEt, —and—NHC(═O)Me. In a further most preferred embodiment R² is not phenylsubstituted with one or two independently selected R⁶ groups, whereineach R⁶ group is selected from C(═O)NH₂, and —C(═O)NHMe.

In one embodiment, the compound of the invention is selected from:

-   9-Allyloxy-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-3-yl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-4-yl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile,-   3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile,-   4-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile,-   [2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(3,5-Dichloro-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Benzofuran-2-yl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-indole-1-carboxylic    acid tert-butyl ester,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(1H-indol-2-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(6-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(6-trifluoromethyl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-3H-imidazol-4-ylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   5-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine-2-carboxylic    acid methylamide,-   2-([1,4]Dioxan-2-ylmethoxy)-9-pent-1-ynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(2-pyridin-2-yl-ethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(2-pyrazin-2-yl-ethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(1H-indol-5-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(5-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(1H-indazol-5-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzamide,-   5-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-2-fluoro-benzamide,-   N-{3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-phenyl}-acetamide,-   9-Cyclopropylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(1-hydroxy-cyclopentylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-pyrimidin-5-yl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Cyclohex-1-enyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(1-methyl-1H-indol-5-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(6-methyl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-2-ylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   5-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pent-4-ynenitrile,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-phenylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-3-ylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   4-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-N-methyl-benzamide,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(2-Chloro-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(1,5-Dimethyl-1H-pyrazol-3-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(1-methyl-1H-pyrazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-[1,2,4]oxadiazol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(4-morpholin-4-yl-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-4-fluoro-benzamide,-   3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-5-fluoro-benzamide,-   9-(3,3-Dimethyl-but-1-ynyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-4-ylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-isoxazol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(3,6-Dihydro-2H-pyran-4-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   5-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine-2-carbonitrile,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(6-isopropoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(6-ethoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(6-morpholin-4-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(2,3-Dimethoxy-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(3-Chloro-2-methoxy-pyridin-4-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(2-methyl-pyridin-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-isonicotinonitrile,-   9-(2,5-Dimethoxy-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(2-ethoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(2,6-Dimethoxy-pyridin-3-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   4-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-nicotinonitrile,-   9-tert-Butoxymethyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(2-pyrrolidin-1-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(6-pyrrolidin-1-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(5-phenyl-oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(5-tert-Butyl-oxazol-2-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(5-Cyclopropyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(5-ethyl-[1,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(5-methyl-[1,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(5-isopropyl-[1,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Cyclopentylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Cyclohexylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-hex-1-ynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-[3-(Benzyl-methyl-amino)-prop-1-ynyl]-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-5-methyl-hex-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Cyclopropyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4-methyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-phenyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(3-Benzylamino-prop-1-ynyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-[(furan-2-ylmethyl)-amino]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(1-ethyl-1H-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-[1-(3-methyl-butyl)-1H-pyrazol-4-yl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(5-methyl-furan-2-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-hex-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(3,5-Dimethyl-1H-pyrazol-4-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(1H-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(1-propyl-1H-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-[2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile,-   2-[2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile,-   9-(5-Cyclopropyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-ethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-pyrimidin-2-ylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-phenylamino-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Cyclopentyloxymethyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Cyclopropylethynyl-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-imidazol-1-yl-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(2-Cyclopropyl-ethyl)-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Cyclopentyloxymethyl-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-propyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Allyloxy-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Allyloxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-yloxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-[3-[(pyridin-3-ylmethyl)-amino]-prop-1-ynyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-pentyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(2-Cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(oxetan-3-yloxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-oxetan-3-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(2,2-Dimethyl-butylamino)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-ethyl-hexylamino)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-ethoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Cyclopropylmethoxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-fluoro-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[3-(2-methoxy-ethoxy)-prop-1-ynyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[3-(2-ethoxy-ethoxy)-prop-1-ynyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[3-(2-fluoro-ethoxy)-prop-1-ynyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(2,2-Dimethyl-propoxymethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Cyclohexyloxymethyl-2-(S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Cyclopropylmethoxymethyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(4,4-Dimethyl-pentyloxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(3-Cyclopropyl-propoxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Cyclohexylamino-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4,4-dimethyl-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-Cyclopentylmethoxymethyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-phenylamino-propyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(Cyclohexyl-methyl-amino)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(Cyclohexylmethyl-amino)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[(tetrahydro-pyran-4-ylmethyl)-amino]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(2,2-Dimethyl-propoxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-([1,4]Dioxan-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(oxetan-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   9-(3-Cyclopropyl-propoxy)-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,

In one embodiment, the compound of the invention is selected from:

-   2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-propoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-isopropoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-propoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,-   2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-isopropoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,    and-   2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one.

In one embodiment, the compound of the invention is9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one.

In another embodiment, the compound of the invention is not9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one.

In one embodiment a compound of the invention is not an isotopicvariant.

In one aspect a compound of the invention is present as the free base.

In one aspect a compound of the invention is a pharmaceuticallyacceptable salt.

In one aspect a compound of the invention is present as the free base ora pharmaceutically acceptable salt.

In one aspect a compound of the invention is a solvate.

In one aspect a compound of the invention is a solvate of apharmaceutically acceptable salt of the compound.

In certain aspects, the present invention provides prodrugs andderivatives of a compound of the invention according to the formulaabove. Prodrugs are derivatives of a compound of the invention, whichhave metabolically cleavable groups and become by solvolysis or underphysiological conditions the compounds of the invention, which arepharmaceutically active, in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like.

Other derivatives of the compounds of this invention have activity inboth their acid and acid derivative forms, but the acid sensitive formoften offers advantages of solubility, tissue compatibility, or delayedrelease in the mammalian organism (see, Bundgard, H. Design of Prodrugs,pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acidderivatives well know to practitioners of the art, such as, for example,esters prepared by reaction of the parent acid with a suitable alcohol,or amides prepared by reaction of the parent acid compound with asubstituted or unsubstituted amine, or acid anhydrides, or mixedanhydrides. Simple aliphatic or aromatic esters, amides and anhydridesderived from acidic groups pendant on the compounds of this inventionare preferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the C₁ to C₈alkyl, C₂-C₈ alkenyl, aryl, C₇-C₁₂ substituted aryl, and C₇C₁₂ arylalkylesters of the compounds of the invention.

While specified groups for each embodiment have generally been listedabove separately, a compound of the invention includes one in whichseveral or each embodiment in the above Formula, as well as otherformulae presented herein, is selected from one or more of particularmembers or groups designated respectively, for each variable. Therefore,this invention is intended to include all combinations of suchembodiments within its scope.

While specified groups for each embodiment have generally been listedabove separately, a compound of the invention may be one for which oneor more variables (for example, R groups) is selected from one or moreembodiments according to any of the Formula (e) listed above. Therefore,the present invention is intended to include all combinations ofvariables from any of the disclosed embodiments within its scope.

Alternatively, the exclusion of one or more of the specified variablesfrom a group or an embodiment, or combinations thereof is alsocontemplated by the present invention.

CLAUSES

-   1. A compound according to Formula Ia:

-    wherein    -   R¹ is H, Me, or halo;    -   L₁ is absent or is —O—, —S—, or —NR^(4a)—;    -   G is        -   R²,        -   —W-L₂-R², or        -   —W-L₃-R³;    -   W is C₁₋₄ alkylene, C₂₋₄ alkenylene having one double bond, or        C₂₋₄ alkynylene having one triple bond;    -   L₂ is absent or is —O—;    -   R² is        -   —H,        -   C₁₋₈ alkyl, optionally substituted with one to three groups            independently selected from            -   OH,            -   halo,            -   CN,            -   C₁₋₆ alkoxy,            -   C₃₋₇ cycloalkyl,            -   4-6 membered heterocycloalkyl comprising one to three                heteroatoms independently selected from S, and O,            -   5-6 membered heteroaryl comprising one to three                heteroatoms independently selected from N, S, and O, and            -   phenyl,        -   C₄₋₇ cycloalkenyl comprising one double bond,        -   5-7 membered heterocycloalkenyl comprising one double bond,            and one to three heteroatoms independently selected from N,            O, and S,        -   C₃₋₇ cycloalkyl optionally substituted with one or more            independently selected R⁵ groups,        -   4-10 membered heterocycloalkyl comprising one to two            heteroatoms independently selected from S, and O, optionally            substituted with one to three independently selected R⁵            groups,        -   5-10 membered heteroaryl comprising one to three heteroatoms            independently selected from N, S, and O optionally            substituted with one to three independently selected R⁶            groups, or        -   C₆₋₁₀ aryl optionally substituted with one or more            independently selected R⁶ groups;    -   L₃ is —NR^(4b)—;    -   R³ is        -   —C₁₋₄ alkyl substituted with            -   C₆₋₁₀ aryl optionally substituted with one or more                independently selected R⁷ groups, or            -   5-10 membered heteroaryl comprising one to three                heteroatoms independently selected from N, S, and O,                optionally substituted with one or more R independently                selected R⁷ groups,        -   5-10 membered heteroaryl comprising one to three heteroatoms            independently selected from N, S, and O, optionally            substituted with one or more independently selected R⁷            group, or        -   C₆₋₁₀ aryl optionally substituted with one or more            independently selected R⁷ groups;    -   Each R^(4a) and R^(4b) is independently selected from H, C₁₋₄        alkyl, and C₃₋₇ cycloalkyl;    -   R⁵ is oxo or R⁶;    -   R⁶ is        -   OH,        -   halo,        -   —NO₂,        -   C₁₋₆ alkyl optionally substituted with one to three groups            independently selected from halo, and OH,        -   C₁₋₆ alkoxy optionally substituted with one to three groups            independently selected from halo, and OH,        -   C₃₋₇ cycloalkyl,        -   —C(═O)OR⁸,        -   —C(═O)NR⁹R¹⁰,        -   —NHC(═O)—C₁₋₄ alkyl,        -   —CN,        -   phenyl,        -   —O-phenyl,        -   4-7 membered heterocycloalkyl comprising one to three            heteroatoms independently selected from N, O, and S, or        -   5-6 membered heteroaryl comprising one to three heteroatoms            independently selected from N, O, and S, optionally            substituted with one or more independently selected C₁₋₄            alkyl, C₁₋₄ alkoxy, CN, halo), and —C(═O)OR¹¹;    -   R⁷ is C₁₋₄ alkyl, or halo; and    -   each of R⁸, R⁹, R¹⁰ and R¹¹ is independently selected from H and        C₁₋₄ alkyl,    -   or a pharmaceutically acceptable salt, or a solvate, or a        solvate of the pharmaceutically acceptable salt.-   2. A compound or pharmaceutically acceptable salt thereof, according    to clause 1, wherein the compound is according to Formula Ib:

-    wherein R¹, L₁ and G are as previously described.-   3. A compound or pharmaceutically acceptable salt thereof, according    to clause 1, wherein the compound is according to Formula Ic:

-    wherein R¹, L₁ and G are as previously described.-   4. A compound or pharmaceutically acceptable salt thereof, according    to any one of clauses 1-3, wherein R¹ is Me, F, or Cl.-   5. A compound or pharmaceutically acceptable salt thereof, according    to any one of clauses 1-3, wherein R¹ is H.-   6. A compound or pharmaceutically acceptable salt thereof, according    to clause 1 or 2, wherein the compound is according to Formula Ha,    IIb or IIc:

-    wherein L₁, and R² are as described in claim 1.-   7. A compound or pharmaceutically acceptable salt thereof, according    to clause 1 or 2, wherein the compound is according to Formula IIIa,    IIIb, or IIIc:

-    wherein L₁, W, L₂, and R² are as described previously.-   8. A compound or pharmaceutically acceptable salt thereof, according    to clause 1 or 2, wherein the compound is according to Formula IVa,    IVb, or IVc:

-    wherein L₁, W, L₃, and R³ are as described in claim 1.-   9. A compound or pharmaceutically acceptable salt thereof, according    to any one of clauses 1-8, wherein L₁ is absent.-   10. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-8, wherein L₁ is —O—.-   11. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-8, wherein L₁ is —NR^(4a)—, and    R^(4a) is H, Me, Et, or cyclopropyl.-   12. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-8, wherein L₁ is —NR^(4a)—, and    R^(4a) is H.-   13. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-5, or 7-11, wherein W is C₁₋₄    alkylene.-   14. A compound or pharmaceutically acceptable salt thereof,    according to clause 13, wherein W is —CH₂—, —CH₂—CH₂—,    —CH₂—CH₂—CH(CH₃)—, —CH₂—CH(—CH₂—CH₃)—, —CH₂—C(CH₃)₂—, or    —CH₂—CH₂—CH₂—.-   15. A compound or pharmaceutically acceptable salt thereof,    according to clause 14, wherein W is —CH₂—CH₂—.-   16. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-5, or 7-11, wherein W is C₂₋₄    alkenylene having one double bond.-   17. A compound or pharmaceutically acceptable salt thereof,    according to clause 16, wherein W is —CH═CH—, —CH₂—CH═CH—, or    —CH═CH—CH₂.-   18. A compound or pharmaceutically acceptable salt thereof,    according to clause 17, wherein W is —CH═CH—.-   19. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-5, or 7-11, wherein W is C₂₋₄    alkynylene having one triple bond.-   20. A compound or pharmaceutically acceptable salt thereof,    according to clause 19, wherein W is —C≡C—, —CH₂—C≡C—, or —C≡C—CH₂—.-   21. A compound or pharmaceutically acceptable salt thereof,    according to clause 20, wherein W is —C≡C—.-   22. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-5, 7, or 9-21, wherein L₂ is —O—.-   23. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-5, 7, or 9-21, wherein L₂ is    absent.-   24. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-5, 7, or 9-21, wherein L₁ and L₂    are absent, and W is —CH₂—, —CH₂—CH₂—, or —CH₂—CH₂—CH₂—.-   25. A compound or pharmaceutically acceptable salt thereof,    according to clause 1-5, 7, or 9-21, wherein L₁ and L₂ are absent,    and W is —CH═CH—, —CH₂—CH═CH—, or —CH═CH—CH₂—.-   26. A compound or pharmaceutically acceptable salt thereof,    according to clause 1-5, 7, or 9-21, wherein L₁ and L₂ are absent,    and W is —C≡C—, —CH₂—C≡C—, or —C≡C—CH₂—.-   27. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-7, or 9-25, wherein R² is H.-   28. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-7, or 9-25, wherein R² is C₁₋₈    alkyl.-   29. A compound or pharmaceutically acceptable salt thereof,    according to clause 28, wherein R² is Me, Et, n-Pr, i-Pr, i-Bu, or    t-Bu.-   30. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-7, or 9-25, wherein R² is C₁₋₈    alkyl substituted with one group selected from OH, halo, CN, C₁₋₆    alkoxy, C₃₋₇ cycloalkyl, 4-6 membered heterocycloalkyl (comprising    one to three heteroatoms independently selected from S, and O), 5-6    membered heteroaryl (comprising one to three heteroatoms    independently selected from N, S, and O), and phenyl.-   31. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-7, or 9-25, wherein R² is Me, Et,    n-Pr, i-Pr, i-Bu, or t-Bu, each of which is substituted with one    group selected from OH, halo, CN, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, 4-6    membered heterocycloalkyl (comprising one to three heteroatoms    independently selected from S, and O), 5-6 membered heteroaryl    (comprising one to three heteroatoms independently selected from N,    S, and O), and phenyl.-   32. A compound or pharmaceutically acceptable salt thereof,    according to any one of clause 30, wherein R² is C₁₋₈ alkyl    substituted with one group selected from OH, F, Cl, CN, —OMe, —OEt,    —Oi-Pr, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl,    tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl,    thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl.-   33. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-7, or 9-25, wherein R² is C₄₋₇    cycloalkenyl comprising one double bond.-   34. A compound or pharmaceutically acceptable salt thereof,    according to clause 33, wherein R² is cyclohexenyl.-   35. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-7, or 9-25, wherein R² is 5-7    membered heterocycloalkenyl comprising one double bond, and one to    three heteroatoms independently selected from N, O, and S.-   36. A compound or pharmaceutically acceptable salt thereof,    according to clause 35, wherein R² is dihydropyranyl.-   37. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-7, or 9-25, wherein R² is C₃₋₇    cycloalkyl.-   38. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-7, or 9-25, wherein R² is C₃₋₇    cycloalkyl substituted with one R⁵ group.-   39. A compound or pharmaceutically acceptable salt thereof,    according to clause 38, wherein R⁵ is oxo, or R⁶ wherein R⁶ is    selected from OH, and C₁₋₆ alkyl.-   40. A compound or pharmaceutically acceptable salt thereof,    according to clauses 37, 38 or 39, wherein R² is cyclopropyl,    cyclobutyl, cyclopentyl or cyclohexyl.-   41. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-7, or 9-25, wherein R² is 4-10    membered heterocycloalkyl comprising one to two heteroatoms    independently selected from S, and O.-   42. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-7, or 9-25, wherein R² is 4-10    membered heterocycloalkyl comprising one to two heteroatoms    independently selected from S, and O, substituted with one R⁵ group.-   43. A compound or pharmaceutically acceptable salt thereof,    according to clause 42, wherein R⁵ is selected from oxo, or R⁶    wherein R⁶ is selected from OH, and C₁₋₆ alkyl.-   44. A compound or pharmaceutically acceptable salt thereof,    according to clause 41, 42 or 43, wherein R² is oxetanyl,    tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl.-   45. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-7, or 9-25, wherein R² is 5-10    membered heteroaryl comprising one to three heteroatoms    independently selected from N, S, and O.-   46. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-7, or 9-25, wherein R² is 5-10    membered heteroaryl comprising one to three heteroatoms    independently selected from N, S, and O, substituted with one or two    independently selected R⁶ groups.-   47. A compound or pharmaceutically acceptable salt thereof,    according to clause 46, wherein each R⁶ is independently selected    from OH, halo, C₁₋₆ alkyl, C₁₋₆ alkyl substituted with one or more    halo, C₁₋₆ alkoxy, —CN, C₃₋₇ cycloalkyl, 4-7 membered    heterocycloalkyl comprising one to three heteroatoms independently    selected from N, O, and S, and phenyl.-   48. A compound or pharmaceutically acceptable salt thereof,    according to clause 45, 46 or 47, wherein R² is furanyl, thienyl,    oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl,    triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.-   49. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-7, or 9-25, wherein R² is C₆₋₁₀    aryl.-   50. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-7, or 9-25, wherein R² is C₆₋₁₀    aryl, substituted with one or two independently selected R⁶ groups.-   51. A compound or pharmaceutically acceptable salt thereof,    according to clause 50, wherein R⁶ is selected from halo, CN, C₁₋₆    alkyl, C₁₋₆ alkoxy, —NHC(═O)—C₁₋₄ alkyl, and —C(═O)NR⁹R¹⁰, wherein    each R⁹ and R¹⁰ is independently selected from H and C₁₋₄ alkyl.-   52. A compound or pharmaceutically acceptable salt thereof,    according to clause 49, 50 or 51, wherein R² is phenyl.-   53. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-5, or 8-21, wherein L₃ is    —NR^(4b)—, and R^(4b) is H, Me, Et, or cyclopropyl.-   54. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-5, or 8-21, wherein R³ is C₁₋₄    alkyl substituted with phenyl, or pyridyl.-   55. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-5, or 8-21, wherein R³ is C₁₋₄    alkyl substituted with phenyl, or pyridyl, each of which is    substituted with Me, Et, F, or Cl-   56. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-5, or 8-21, wherein R³ is 5-10    membered heteroaryl comprising one to three heteroatoms    independently selected from N, S, and O.-   57. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-5, or 8-21, wherein R³ is 5-10    membered heteroaryl comprising one to three heteroatoms    independently selected from N, S, and O, substituted with one or    more independently selected R⁷ groups.-   58. A compound or pharmaceutically acceptable salt thereof,    according to clause 57 wherein R⁷ is selected from Me, Et, F, and    Cl.-   59. A compound or pharmaceutically acceptable salt thereof,    according to clause 56, 57, or 58 wherein R³ is pyridyl.-   60. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-5, or 8-21, wherein R³ is C₆₋₁₀    aryl.-   61. A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-5, or 8-21, wherein R³ is C₆₋₁₀    aryl, substituted with one or more independently selected R⁷ groups.-   62. A compound or pharmaceutically acceptable salt thereof,    according to clause 61, wherein R⁷ is selected from Me, Et, F, and    Cl.-   63. A compound or pharmaceutically acceptable salt thereof,    according to clause 60, 61, or 62, wherein R³ is phenyl.-   64. A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is according to Formula    Va:

-    wherein R² is as described previously.-   65. A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is according to Formula    Vb:

-    wherein R² is as described previously.-   66. A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is according to Formula    Vc:

-    wherein R² is as described previously.-   67. A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is according to Formula    Vd:

-    wherein R² is as described previously.-   68. A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is according to Formula    VIa:

-    wherein R² is as described previously.-   69. A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is according to Formula    VIb:

-    wherein R² is as described previously.-   70. A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is according to Formula    VIc:

-    wherein R² is as described previously.-   71. A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is according to Formula    VId:

-    wherein R² is as described previously.-   72. A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is according to Formula    VIIa:

-    wherein R² is as described previously.-   73. A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is according to Formula    VIIb:

-    wherein R² is as described previously.-   74. A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is according to Formula    VIIc:

-    wherein R² is as described previously.-   75. A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is according to Formula    VIId:

-    wherein R² is as described previously.-   76. A compound or pharmaceutically acceptable salt thereof,    according to clause 64, 65, 68, 69, 72, or 73, wherein R² is C₃₋₇    cycloalkyl.-   77. A compound or pharmaceutically acceptable salt thereof,    according to clause 64, 65, 68, 69, 72, or 73, wherein R² is C₃₋₇    cycloalkyl substituted with one R⁵ group.-   78. A compound or pharmaceutically acceptable salt thereof,    according to clause 77, wherein R⁵ is oxo, or R⁶ wherein R⁶ is OH,    or C₁₋₆ alkyl.-   79. A compound or pharmaceutically acceptable salt thereof,    according to clause 76, 77 or 78, wherein R² is cyclopropyl,    cyclobutyl, cyclopentyl or cyclohexyl.-   80. A compound or pharmaceutically acceptable salt thereof,    according to clause 66, 67, 70, 71, 74, or 75, wherein R² is 5-10    membered heteroaryl comprising one to three heteroatoms    independently selected from N, S, and O.-   81. A compound or pharmaceutically acceptable salt thereof,    according to clause 66, 67, 70, 71, 74, or 75, wherein R² is 5-10    membered heteroaryl comprising one to three heteroatoms    independently selected from N, S, and O, substituted with one or two    independently selected R⁶ groups.-   82. A compound or pharmaceutically acceptable salt thereof,    according to clause 81, wherein R⁶ is selected from OH, halo, C₁₋₆    alkyl, C₁₋₆ alkyl substituted with one or more halo, C₁₋₆ alkoxy,    —CN, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl comprising one    to three heteroatoms independently selected from N, O, and S, and    phenyl.-   83. A compound or pharmaceutically acceptable salt thereof,    according to clause 80, 81 or 82, wherein R² is furanyl, thienyl,    oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl,    triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.-   84. A compound or pharmaceutically acceptable salt thereof,    according to clause 66, 67, 70, 71, 74, or 75, wherein R² is C₆₋₁₀    aryl.-   85. A compound or pharmaceutically acceptable salt thereof,    according to clause 66, 67, 70, 71, 74, or 75, wherein R² is C₆₋₁₀    aryl substituted with one or two independently selected R⁶ groups.-   86. A compound or pharmaceutically acceptable salt thereof,    according to clause 85, wherein R⁶ is selected from halo, CN, C₁₋₆    alkyl, C₁₋₆ alkoxy, —NHC(═O)—C₁₋₄ alkyl, and —C(═O)NR⁹R¹⁰, and each    R⁹ and R¹⁰ is independently selected from H and C₁₋₄ alkyl.-   87. A compound or pharmaceutically acceptable salt thereof,    according to clause 84, 85 or 86, wherein R² is phenyl.-   88. A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is    9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one.-   89. A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is not    9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one.

PHARMACEUTICAL COMPOSITIONS

When employed as a pharmaceutical, a compound of the invention istypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared in a manner well known in thepharmaceutical art and comprise at least one active compound. Generally,a compound of the invention is administered in a pharmaceuticallyeffective amount. The amount of a compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound-administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

The pharmaceutical compositions of the invention can be administered bya variety of routes including oral, rectal, transdermal, subcutaneous,intra-articular, intravenous, intramuscular, intranasal and inhalation.Depending on the intended route of delivery, a compound of thisinvention is preferably formulated as either injectable or oralcompositions or as salves, as lotions or as patches all for transdermaladministration.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient, vehicle orcarrier. Typical unit dosage forms include prefilled, premeasuredampules or syringes of the liquid compositions or pills, tablets,capsules or the like in the case of solid compositions. In suchcompositions, a compound of the invention is usually a minor component(from about 0.1 to about 50% by weight or preferably from about 1 toabout 40% by weight) with the remainder being various vehicles orcarriers and processing aids helpful for forming the desired dosingform.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable carrier and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s), generally in an amountranging from about 0.01 to about 20% by weight, preferably from about0.1 to about 20% by weight, preferably from about 0.1 to about 10% byweight, and more preferably from about 0.5 to about 15% by weight. Whenformulated as a ointment, the active ingredients will typically becombined with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream with,for example an oil-in-water cream base. Such transdermal formulationsare well-known in the art and generally include additional ingredientsto enhance the dermal penetration of stability of the active ingredientsor the formulation. All such known transdermal formulations andingredients are included within the scope of this invention.

A compound of the invention can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

A compound of the invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The following formulation examples illustrate representativepharmaceutical compositions that may be prepared in accordance with thisinvention. The present invention, however, is not limited to thefollowing pharmaceutical compositions.

Formulation 1—Tablets

A compound of the invention may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate may be added as a lubricant. The mixture may beformed into 240-270 mg tablets (80-90 mg of active amide compound pertablet) in a tablet press.

Formulation 2—Capsules

A compound of the invention may be admixed as a dry powder with a starchdiluent in an approximate 1:1 weight ratio. The mixture may be filledinto 250 mg capsules (125 mg of active amide compound per capsule).

Formulation 3—Liquid

A compound of the invention (125 mg), may be admixed with sucrose (1.75g) and xanthan gum (4 mg) and the resultant mixture may be blended,passed through a No. 10 mesh U.S. sieve, and then mixed with apreviously made solution of microcrystalline cellulose and sodiumcarboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10mg), flavor, and color may be diluted with water and added withstirring. Sufficient water may then be added with stirring. Sufficientwater may be then added to produce a total volume of 5 mL.

Formulation 4—Tablets

A compound of the invention may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate may be added as a lubricant. The mixture is formedinto 450-900 mg tablets (150-300 mg of active amide compound) in atablet press.

Formulation 5—Injection

A compound of the invention may be dissolved or suspended in a bufferedsterile saline injectable aqueous medium to a concentration ofapproximately 5 mg/mL.

Formulation 6—Topical

Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted atabout 75° C. and then a mixture of a compound of the invention (50 g)methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate(10 g), and propylene glycol (120 g) dissolved in water (about 370 g)may be added and the resulting mixture may be stirred until it congeals.

METHODS OF TREATMENT

A compound of the invention may be used as a therapeutic agent for thetreatment of conditions in mammals that are causally related orattributable to aberrant activity of GPR84 and/or aberrant GPR84expression and/or aberrant GPR84 distribution.

Accordingly, a compound and pharmaceutical compositions of the inventionfind use as therapeutics for the prophylaxis and/or treatment ofinflammatory conditions (e.g. inflammatory bowel diseases (IBD),rheumatoid arthritis, vasculitis, lung diseases (e.g. chronicobstructive pulmonary disease (COPD) and lung interstitial diseases(e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatoryconditions, infectious diseases, autoimmune diseases, endocrine and/ormetabolic diseases, and/or diseases involving impairment of immune cellfunctions, in mammals including humans.

Accordingly, in one aspect, the present invention provides the compoundof the invention, or a pharmaceutical composition comprising thecompound of the invention for use as a medicament.

In another aspect, the present invention provides the compound of theinvention, or a pharmaceutical composition comprising the compound ofthe invention for use in the manufacture of a medicament.

In yet another aspect, the present invention provides a method oftreating a mammal having, or at risk of having a disease disclosedherein. In a particular aspect, the present invention provides a methodof treating a mammal having, or at risk of having inflammatoryconditions (e.g. inflammatory bowel diseases (IBD), rheumatoidarthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonarydisease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonaryfibrosis (IPF))), neuroinflammatory conditions, infectious diseases,autoimmune diseases, endocrine and/or metabolic diseases, and/ordiseases involving impairment of immune cell functions, in mammalsincluding humans.

In one aspect, the present invention provides the compound of theinvention, or a pharmaceutical composition comprising the compound ofthe invention for use as a medicine for the prophylaxis and/or treatmentof inflammatory conditions. In a specific embodiment, the inflammatorycondition is selected from inflammatory bowel disease (IBD), rheumatoidarthritis, vasculitis, chronic obstructive pulmonary disease (COPD), andidiopathic pulmonary fibrosis (IPF).

In another aspect, the present invention provides the compound of theinvention, or a pharmaceutical composition comprising the compound ofthe invention for use in the manufacture of a medicament for theprophylaxis and/or treatment of inflammatory conditions. In a specificembodiment, the inflammatory condition is selected from inflammatorybowel disease (IBD), rheumatoid arthritis, vasculitis, chronicobstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis(IPF).

In additional method of treatment aspects, this invention providesmethods of treatment and/or prophylaxis of a mammal susceptible to orafflicted with inflammatory conditions, which method comprisesadministering an effective amount of a compound of the invention, or oneor more of the pharmaceutical compositions herein described. In aspecific embodiment, the inflammatory condition is selected frominflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis,chronic obstructive pulmonary disease (COPD), and idiopathic pulmonaryfibrosis (IPF).

In another aspect, the present invention provides a method of treating amammal having, or at risk of having a disease selected from inflammatoryconditions (for example inflammatory bowel diseases (IBD), rheumatoidarthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonarydisease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonaryfibrosis (IPF))), neuroinflammatory conditions, infectious diseases,autoimmune diseases, endocrine and/or metabolic diseases, and/ordiseases involving impairment of immune cell functions.

In one aspect, the present invention provides the compound of theinvention, or a pharmaceutical composition comprising the compound ofthe invention for use as a medicine for the prophylaxis and/or treatmentof neuroinflammatory conditions, Guillain-Barré syndrome (GBS), multiplesclerosis, axonal degeneration, autoimmune encephalomyelitis.

In another aspect, the present invention provides the compound of theinvention, or a pharmaceutical composition comprising the compound ofthe invention for use in the manufacture of a medicament for theprophylaxis and/or treatment of neuroinflammatory conditions,Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration,autoimmune encephalomyelitis.

In additional method of treatment aspects, this invention providesmethods of treatment and/or prophylaxis of a mammal susceptible to orafflicted with neuroinflammatory conditions, Guillain-Barré syndrome(GBS), multiple sclerosis, axonal degeneration, autoimmuneencephalomyelitis, which method comprises administering an effectiveamount of a compound of the invention, or one or more of thepharmaceutical compositions herein described.

In one aspect, the present invention provides the compound of theinvention, or a pharmaceutical composition comprising the compound ofthe invention for use as a medicine for the prophylaxis and/or treatmentof infectious disease. In a specific embodiment, the infectious diseasesis selected from sepsis, septicemia, endotoxemia, systemic inflammatoryresponse syndrome (SIRS), gastritis, enteritis, enterocolitis,tuberculosis, and other infections involving, for example, Yersinia,Salmonella, Chlamydia, Shigella, enterobacteria species.

In another aspect, the present invention provides the compound of theinvention, or a pharmaceutical composition comprising the compound ofthe invention for use in the manufacture of a medicament for theprophylaxis and/or treatment of infectious disease. In a specificembodiment, the infectious diseases is selected from sepsis, septicemia,endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis,enteritis, enterocolitis, tuberculosis, and other infections involving,for example, Yersinia, Salmonella, Chlamydia, Shigella, enterobacteriaspecies.

In additional method of treatment aspects, this invention providesmethods of treatment and/or prophylaxis of a mammal susceptible to orafflicted with infectious disease, which method comprises administeringan effective amount of a compound of the invention, or one or more ofthe pharmaceutical compositions herein described. In a specificembodiment, the infectious diseases is selected from sepsis, septicemia,endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis,enteritis, enterocolitis, tuberculosis, and other infections involving,for example, Yersinia, Salmonella, Chlamydia, Shigella, enterobacteriaspecies.

In one aspect, the present invention provides the compound of theinvention, or a pharmaceutical composition comprising the compound ofthe invention for use as a medicine for the prophylaxis and/or treatmentof autoimmune diseases, and/or diseases involving impairment of immunecell functions. In a specific embodiment, the autoimmune diseases and/ordiseases involving impairment of immune cell functions is selected fromCOPD, asthma, psoriasis, systemic lupus erythematosis, type I diabetesmellitus, vasculitis and inflammatory bowel disease.

In another aspect, the present invention provides the compound of theinvention, or a pharmaceutical composition comprising the compound ofthe invention for use in the manufacture of a medicament for theprophylaxis and/or treatment of autoimmune diseases and/or diseasesinvolving impairment of immune cell functions. In a specific embodiment,the autoimmune diseases, and/or diseases involving impairment of immunecell functions is selected from COPD, asthma, psoriasis, systemic lupuserythematosis, type I diabetes mellitus, vasculitis and inflammatorybowel disease.

In additional method of treatment aspects, this invention providesmethods of treatment and/or prophylaxis of a mammal susceptible to orafflicted with autoimmune diseases and/or diseases involving impairmentof immune cell functions, which method comprises administering aneffective amount of a compound of the invention, or one or more of thepharmaceutical compositions herein described. In a specific embodiment,the autoimmune diseases and/or diseases involving impairment of immunecell functions is selected from COPD, asthma, psoriasis, systemic lupuserythematosis, type I diabetes mellitus, vasculitis and inflammatorybowel disease.

In one aspect, the present invention provides the compound of theinvention, or a pharmaceutical composition comprising the compound ofthe invention for use as a medicine for the prophylaxis and/or treatmentof endocrine and/or metabolic diseases. In a specific embodiment, theendocrine and/or metabolic diseases is selected from hypothyroidism,congenital adrenal hyperplasia, diseases of the parathyroid gland,diabetes mellitus, diseases of the adrenal glands (including Cushing'ssyndrome and Addison's disease), ovarian dysfunction (includingpolycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU),diabetes, hyperlipidemia, gout, and rickets.

In another aspect, the present invention provides the compound of theinvention, or a pharmaceutical composition comprising the compound ofthe invention for use in the manufacture of a medicament for theprophylaxis and/or treatment of endocrine and/or metabolic diseases. Ina specific embodiment, the endocrine and/or metabolic diseases isselected from hypothyroidism, congenital adrenal hyperplasia, diseasesof the parathyroid gland, diabetes mellitus, diseases of the adrenalglands (including Cushing's syndrome and Addison's disease), ovariandysfunction (including polycystic ovary syndrome), cystic fibrosis,phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

In additional method of treatment aspects, this invention providesmethods of treatment and/or prophylaxis of a mammal susceptible to orafflicted with endocrine and/or metabolic diseases, which methodcomprises administering an effective amount of a compound of theinvention, or one or more of the pharmaceutical compositions hereindescribed. In a specific embodiment, the endocrine and/or metabolicdiseases is selected from hypothyroidism, congenital adrenalhyperplasia, diseases of the parathyroid gland, diabetes mellitus,diseases of the adrenal glands (including Cushing's syndrome andAddison's disease), ovarian dysfunction (including polycystic ovarysyndrome), cystic fibrosis, phenylketonuria (PKU), diabetes,hyperlipidemia, gout, and rickets.

As a further aspect of the invention there is provided a compound of theinvention for use as a medicament especially in the treatment orprevention of the aforementioned conditions and diseases. Also providedherein is the use of the compound in the manufacture of a medicament forthe treatment or prevention of one of the aforementioned conditions anddiseases.

A particular regimen of the present method comprises the administrationto a subject in suffering from an inflammatory condition, of aneffective amount of a compound of the invention for a period of timesufficient to reduce the level of inflammation in the subject, andpreferably terminate, the processes responsible for said inflammation. Aspecial embodiment of the method comprises administering of an effectiveamount of a compound of the invention to a subject suffering from orsusceptible to the development of inflammatory condition, for a periodof time sufficient to reduce or prevent, respectively, inflammation ofsaid patient, and preferably terminate, the processes responsible forsaid inflammation.

Injection dose levels range from about 0.1 mg/kg/h to at least 10mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h.A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more mayalso be administered to achieve adequate steady state levels. Themaximum total dose is not expected to exceed about 2 g/day for a 40 to80 kg human patient.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses.

When used to prevent the onset of a condition, a compound of theinvention will be administered to a patient at risk for developing thecondition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Patients at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

A compound of the invention can be administered as the sole active agentor it can be administered in combination with other therapeutic agents,including other compounds that demonstrate the same or a similartherapeutic activity, and that are determined to be safe and efficaciousfor such combined administration. In a specific embodiment,co-administration of two (or more) agents allows for significantly lowerdoses of each to be used, thereby reducing the side effects seen.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prevention of aninflammatory condition; particular agents include, but are not limitedto, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g.prednisolone or dexamethasone), cyclophosphamide, cyclosporin A,tacrolimus, Mycophenolate Mofetil, muromonab-CD3 (OKT3, e.g.Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, andpiroxicam.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prevention ofarthritis (e.g. rheumatoid arthritis); particular agents include but arenot limited to analgesics, non-steroidal anti-inflammatory drugs(NSAIDS), steroids, synthetic DMARDS (for example but without limitationmethotrexate, leflunomide, sulfasalazine, auranofin, sodiumaurothiomalate, penicillamine, chloroquine, hydroxychloroquine,azathioprine, and cyclosporin), and biological DMARDS (for example butwithout limitation Infliximab, Etanercept, Adalimumab, Rituximab,Golimumab, Certolizumab pegol, Tocilizumab, Interleukin 1 blockers andAbatacept).

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prevention ofautoimmune diseases; particular agents include but are not limited to:glucocorticoids, cytostatic agents (e.g. purine analogs), alkylatingagents, (e.g nitrogen mustards (cyclophosphamide), nitrosoureas,platinum compounds, and others), antimetabolites (e.g. methotrexate,azathioprine and mercaptopurine), cytotoxic antibiotics (e.g.dactinomycin anthracyclines, mitomycin C, bleomycin, and mithramycin),antibodies (e.g., anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonalantibodies, Atgam® and Thymoglobuline®), cyclosporin, tacrolimus,rapamycin (sirolimus), interferons (e.g. IFN-β), TNF binding proteins(e.g. infliximab (Remicade™), etanercept (Enbrel™), or adalimumab(Humira™)), mycophenolate, Fingolimod, and Myriocin.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prevention ofinfectious diseases; particular agents include but are not limited toantibiotics. In a particular embodiment, a compound of the invention isco-administered with another therapeutic agent for the treatment and/orprevention of infections of any organ of the human body; particularagents include but are not limited to: aminoglycosides, ansamycins,carbacephem, carbapenems, cephalosporins, glycopeptides, lincosamides,macrolides, monobactams, nitrofurans, penicillins, polypeptides,quinolones, sulfonamides, tetracyclins, anti-mycobacterial agents, aswell as chloramphenicol, fosfomycin, linezolid, metronidazole,mupirocin, rifamycin, thiamphenicol and tinidazole.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prevention ofvasculitis, particular agents include but are not limited to steroids(for example prednisone, prednisolone), cyclophosphamide and eventuallyantibiotics in case of cutaneous infections (for example cephalexin)

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prevention of IPF,particular agents include but are not limited to pirfenidone andbosentan.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prevention of asthmaand/or rhinitis and/or COPD; particular agents include but are notlimited to: beta₂-adrenoceptor agonists (e.g. salbutamol, levalbuterol,terbutaline and bitolterol), epinephrine (inhaled or tablets),anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral orinhaled) Long-acting β₂-agonists (e.g. salmeterol, formoterol,bambuterol, and sustained-release oral albuterol), combinations ofinhaled steroids and long-acting bronchodilators (e.g.fluticasone/salmeterol, budesonide/formoterol), leukotriene antagonistsand synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton),inhibitors of mediator release (e.g. cromoglycate and ketotifen),phosphodiesterase-4 inhibitors (e.g. Roflumilast), biological regulatorsof IgE response (e.g. omalizumab), antihistamines (e.g. ceterizine,cinnarizine, fexofenadine), and vasoconstrictors (e.g. oxymethazoline,xylomethazoline, nafazoline and tramazoline).

Additionally, a compound of the invention may be administered incombination with emergency therapies for asthma and/or COPD, suchtherapies include oxygen or heliox administration, nebulized salbutamolor terbutaline (optionally combined with an anticholinergic (e.g.ipratropium), systemic steroids (oral or intravenous, e.g. prednisone,prednisolone, methylprednisolone, dexamethasone, or hydrocortisone),intravenous salbutamol, non-specific beta-agonists, injected or inhaled(e.g. epinephrine, isoetharine, isoproterenol, metaproterenol),anticholinergics (IV or nebulized, e.g. glycopyrrolate, atropine,ipratropium), methylxanthines (theophylline, aminophylline,bamiphylline), inhalation anesthetics that have a bronchodilatory effect(e.g. isoflurane, halothane, enflurane), ketamine, and intravenousmagnesium sulfate.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prevention ofinflammatory bowel disease (IBD); particular agents include but are notlimited to: glucocorticoids (e.g. prednisone, budesonide) syntheticdisease modifying, immunomodulatory agents (e.g. methotrexate,leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurineand ciclosporin) and biological disease modifying, immunomodulatoryagents (infliximab, adalimumab, rituximab, and abatacept).

By co-administration is included any means of delivering two or moretherapeutic-agents to the patient as part of the same treatment regime,as will be apparent to the skilled person. Whilst the two or more agentsmay be administered simultaneously in a single formulation this is notessential. The agents may be administered in different formulations andat different times.

GENERAL SYNTHETIC PROCEDURES General

A compound of the invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Wiley-Blackwell; 4th Revised editionedition (2006), and references cited therein.

The following methods are presented with details as to the preparationof representative 6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one that havebeen listed hereinabove. A compound of the invention may be preparedfrom known or commercially available starting materials and reagents byone skilled in the art of organic synthesis.

All reagents were of commercial grade and were used as received withoutfurther purification, unless otherwise stated. Commercially availableanhydrous solvents were used for reactions conducted under inertatmosphere. Reagent grade solvents were used in all other cases, unlessotherwise specified. Column chromatography was performed on silicastandard (30-70 μm). Thin layer chromatography was carried out usingpre-coated silica gel 60 F-254 plates (thickness 0.25 mm) ¹H NMR spectrawere recorded on a Bruker Advance 400 NMR spectrometer (400 MHz) or aBruker Advance 300 NMR spectrometer (300 MHz). Chemical shifts (δ) for¹H NMR spectra are reported in parts per million (ppm) relative totetramethylsilane (δ 0.00) or the appropriate residual solvent peak asinternal reference. Multiplicities are given as singlet (s), doublet(d), doublet of doublet (dd), triplet (t), quartet (q), multiplet (m)and broad (br). Electrospray MS spectra were obtained either on a Watersplatform LC/MS spectrometer or on an Agilent 1100 Series LC/MSD.Analytic LCMS: Columns used, Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mmID×50 mm L or Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID×30 mm L orWaters XBridge C18 3.5 μm, 2.1 mm ID×50 mm L All the methods are usingMeCN/H₂O gradients. MeCN and H₂O contain either 0.1% Formic Acid or NH₃(10 mM). Preparative LCMS: Column used, Waters XBridge Prep C18 μm ODB30 mm ID×100 mm L. All the methods are using either MeOH/H₂O or MeCN/H₂Ogradients. MeOH, MeCN and H₂O contain either 0.1% Formic Acid or 0.1%Diethylamine. Analytic chiral LC: Column used, Chiralpak IA 5 μm 250×4.6mm. Microwave heating was performed with a Biotage Initiator.

TABLE I List of abbreviations used in the experimental section: μLmicroliter AcOH Acetic acid Aq. aqueous ATP Adenosine 5′-TriphosphateBINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl Boctert-Butyloxy-carbonyl Boc₂O Di-tert-butyl dicarbonate br s broadsinglet Calcd calculated Cat. Catalytic amount D doublet Dd Doublet ofdoublet DCC N,N′-Dicyclohexylcarbodiimide DCE 1,2-Dichloroethane DCMDichloromethane DIAD Diisopropyl azodicarboxylate DIPEAN,N-diisopropylethylamine DMAP 4-Dimethylaminopyridine DMEDimethoxyethane DMF N,N-dimethylformamide DMSO Dimethylsulfoxide DPBSDulbecco′s Phosphate-Buffered Saline DPPF1,1′-Bis(diphenylphosphino)ferrocene EtOAc Ethyl acetate Et₂O Diethylether eq. equivalent g gram GTP□S guanosine5′-O-[gamma-thio]triphosphate h hour H Heptane HPLC High-performanceliquid chromatography iPrOH isopropanol iPr₂O Diisopropyl ether KHMDSPotassium hexamethyldisilazane LCMS Liquid Chromatography- MassSpectrometry L Liter M multiplet MeOH Methanol MeCN Acetonitrile MeIMethyl iodide MEK Methyl ethyl ketone Mg milligram Min minute mLmilliliter Mmol millimole MS mass spectrometry MW Molecular weight MW(calc) Molecular weight calculated MW (obs) Molecular weight observedNADP Nicotinamide adenine dinucleotide phosphate NEAA Non-EssentialAmino Acid NMP N-Methyl-2-pyrrolidone NMR Nuclear Magnetic Resonnanceobsd observed Pd(OAc)₂ Palladium(II) acetate Pd(PPh₃)₄Tetrakis(triphenylphosphine)palladium(0) Pd/C Palladium on Carbon 10%ppm part-per-million q quadruplet rpm revolutions per minute RT Roomtemperature Rt retention time RuPhos2-Dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl s singlet SMStarting material spA Scintillation proximity assay SPE Solid phaseextraction STAB sodiumtriacetoxyborohydride t triplet TBAFTetra-n-butylammonium fluoride TEA Triethylamine TFA Trifluoroaceticacid THF Tetrahydrofuran TLC Thin layer chromatography

General Synthetic Method Intermediates

The intermediates to prepare the compounds according to the inventioncan be produced according to the following schemes.

Intermediate 1 [2-(3-methoxy-phenyl)-ethyl]-urea

A solution of 3-methoxyphenethylamine (100 g, 661.3 mmol, 1 eq.), urea(157.3 g, 2619.0 mmol, 4 eq.), AcOH (36 mL) and aq. HCl (12 mL) in H₂O(800 mL) was heated under reflux for 5 days. The reaction mixture wascooled to RT, the solid was filtered off, washed with water and dried toafford intermediate 1.

(¹H, CDCl₃) δ (ppm): 7.24 (1H, t), 6.82-6.77 (3H, m), 5.10 (1H, br s),4.52 (2H, br), 3.81 (1H, s), 3.42 (2H, br t), 2.80 (2H, t)

Intermediate 2 [2-(3-hydroxy-phenyl)-ethyl]-urea

A solution of intermediate 1 (72 g, 370.7 mmol) in concentrated HBr (500mL) was heated under reflux overnight. The reaction mixture was broughtto basic pH by addition of NaHCO₃ and extracted with EtOAc. The organiclayer was dried over MgSO₄ and concentrated under vacuum to affordintermediate 2. (¹H, MeOD-d₄) δ (ppm): 7.15 (1H, t), 6.76-6.68 (3H, m),3.40-3.36 (2H, t), 2.77-2.74 (2H, t)

Intermediate 3 [2-(3-allyloxy-phenyl)-ethyl]urea

To a solution of intermediate 2 (45 g, 249.7 mmol, 1 eq.) and K₂CO₃(103.5 g, 749.1 mmol, 3 eq.) in anhydrous DMF (300 mL) under a nitrogenatmosphere, was added allylbromide (50.5 mL, 499.4 mmol, 2 eq.). Thereaction mixture was stirred for 2.5 days, then DMF was evaporated todryness. The residue was dissolved in EtOAc, washed with saturatedNa₂CO₃, brine, dried over MgSO₄ and concentrated under vacuum to affordintermediate 3.

(¹H, MeOD-d₄) δ (ppm): 7.24 (1H, t), 6.87-6.81 (3H, m), 6.16-6.06 (1H,m), 5.45 (1H, dd), 5.29 (1H, dd), 4.59-4.57 (2H, m), 3.38 (2H, t), 2.80(2H, t)

Intermediate 4 1-[2-(3-allyloxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione

Sodium (20.06 g, 872 mmol, 1 eq.) was dissolved in EtOH (1.4 L). Diethylmalonate (132.4 mL, 872 mmol, 1 eq.) was added and the reaction mixturewas heated under reflux for 1 h. Intermediate 3 (96 g, 436 mmol, 0.5eq.) in EtOH (300 mL) was added and the reaction mixture was heatedunder reflux for 12 h. The reaction was cooled to RT, 1N aq. HCl wasadded and the precipitate was filtered, washed with water and dried toafford intermediate 4.

(¹H, CDCl₃) δ (ppm): 8.40 (1H, br s), 7.25 (1H, t), 6.88-6.82 (3H, m),6.14-6.04 (1H, m), 5.45 (1H, dd), 5.32 (1H, dd), 4.58-4.56 (2H, m), 4.13(2H, t), 3.64 (2H, s), 2.92 (2H, t)

MW (calcd): 288.3; MW (obsd): 289.3 (M+1)

Intermediate 59-allyloxy-2-chloro-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

A solution of intermediate 4 (20 g, 69.4 mmol, 1 eq.) in POCl₃ (150 mL)was stirred at 50° C. for 3 days. POCl₃ was evaporated under vacuum andthe residue was dissolved in DCM and quenched with saturated NaHCO₃. Theorganic layer was washed with water, dried over MgSO₄ and concentratedto afford intermediate 5.

(¹H, CDCl₃) δ (ppm): 7.71 (2H, d), 6.97 (1H, dd), 6.86 (1H, d), 6.71(1H, s), 6.13-6.04 (1H, m), 5.47 (1H, dd), 5.36 (1H, dd), 4.67-4.65 (2H,m), 4.27 (2H, t), 3.05 (2H, t)

MW (calcd): 288.7; MW (obsd): 289.3 (M+1)

General Methods General Method A

To a solution of NaH (2 eq., 60% in mineral oil) in anhydrous DCM at 0°C., is added 2-hydroxymethyl-[1,4]dioxane (2 eq.) with the appropriatechirality, after 15 min, intermediate 5 (1 eq.) is added at 0° C., andthe reaction is stirred at RT until completion. Saturated NH₄Cl is addedto the reaction mixture, the organic layer is washed with water, driedover MgSO₄ and concentrated. The desired product is purified by flashchromatography on silica gel.

2-Hydroxymethyl-[1,4]dioxane, (R) 2-hydroxymethyl-[1,4]dioxane and (S)2-hydroxymethyl-[1,4]dioxane are commercially available or can easily beprepared [Young Kim et al; Bioorganic & Medicinal Chemistry 15 (2007)2667-2679].

Illustrative Synthesis of General Method A Compound 1189-allyloxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

A solution of (R) 2-hydroxymethyl-[1,4]dioxane (56.6 g, 479 mmol, 2 eq.)and NaH (19.9 g, 479 mmol, 2 eq., 60% in mineral oil) in anhydrous DCM(300 mL) was stirred for 30 min at 0° C. Intermediate 5 (69.2 g, 240mmol, 1 eq.) in solution in anhydrous DCM (700 mL) was added at 0° C.The reaction mixture was stirred for 2 h. Saturated NH₄Cl was added, theorganic layer was washed with water, dried over MgSO₄ and evaporated todryness. The crude product was purified by flash chromatography onsilica gel (MeOH/DCM) to afford compound 118.

(¹H, CDCl₃) δ (ppm): 7.66 (1H, d), 6.94 (1H, dd), 6.83 (1H, d), 6.32(1H, s), 6.15-6.03 (1H, m), 5.47 (1H, dd), 5.37 (1H, dd), 4.65-4.63 (2H,m), 4.51-4.39 (2H, m), 4.23 (2H, t), 4.06-3.98 (1H, m), 3.92-3.47 (6H,m), 3.01 (2H, t)

Compound 19-allyloxy-2-(-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Compound 1 was prepared using general method A starting from2-hydroxymethyl-[1,4]dioxane.

(¹H, CDCl₃) δ (ppm): 7.66 (1H, d), 6.94 (1H, dd), 6.83 (1H, d), 6.32(1H, s), 6.11-6.04 (1H, m), 5.47 (1H, dd), 5.35 (1H, dd), 4.65-4.63 (2H,m), 4.491-4.40 (2H, m), 4.22 (2H, t), 4.02-3.99 (1H, m), 3.90-3.46 (6H,m), 3.00 (2H, t)

MW (calcd): 370.4; MW (obsd): 371.4 (M+1)

Compound 1179-allyloxy-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Compound 117 was prepared using general method A starting from (S)2-hydroxymethyl-[1,4]dioxane.

(¹H, CDCl₃) δ (ppm): 7.66 (1H, d), 6.94 (1H, dd), 6.83 (1H, d), 6.31(1H, s), 6.12-6.04 (1H, m), 5.49 (1H, dd), 5.36 (1H, dd), 4.65-4.63 (2H,m), 4.50-4.42 (2H, m), 4.23 (2H, t), 4.04-4.00 (1H, m), 3.91-3.50 (6H,m), 3.01 (2H, t)

MW (calcd): 370.4; MW (obsd): 371.2 (M+1)

General Method B

To a suspension of compound 1, 117 or 118 (1 eq.) in a mixture ofDCM/MeOH (1/1) is added K₂CO₃ (2 eq.) and Pd(PPh₃)₄ (0.05 eq.). Thereaction mixture is degassed before stirring at RT. After completion,water is added to the reaction mixture and the aqueous layer isseparated. The pH of the aqueous solution is adjusted to pH 1 with 2Maq. HCl. The precipitate is filtered off, washed with water and dried toafford intermediate 6, 7 or 8.

Illustrative Synthesis of General Method B Intermediate 62-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-hydroxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

To a suspension of compound 118 (31.15 g, 84.2 mmol, 1 eq.) in a mixtureof DCM/MeOH (1/1, 800 mL) was added K₂CO₃ (23.2 g, 138.2 mmol, 2 eq.)and Pd(PPh₃)₄ (4.86 g, 4.21 mmol, 0.05 eq.). The reaction mixture wasstirred at RT for 2 h. Water (800 mL) was added, and the aqueous layerwas separated. The pH of the aqueous solution is adjusted to pH 1 with 2M aq. HCl. The precipitate was filtered off, washed with water and driedto afford intermediate 6.

(¹H, DMSO-d6) δ (ppm): 7.84 (1H, d), 6.77 (1H, dd), 6.74 (1H, d), 6.45(1H, s), 4.25-4.23 (2H, m), 3.99 (2H, t), 3.87-3.75 (3H, m), 3.68-3.58(2H, m), 3.52-3.46 (1H, m), 3.40-3.30 (1H, m), 2.91 (2H, t)

MW (calcd): 330.4; MW (obsd): 331.3 (M+1)

Intermediate 72-((R)-1-[1,4]dioxan-2-ylmethoxy)-9-hydroxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Intermediate 7 was prepared using general method B starting fromcompound 117.

(¹H, DMSO-d6) δ (ppm): 7.83 (1H, d), 6.77 (1H, dd), 6.74 (1H, d), 6.44(1H, s), 4.27-4.20 (2H, m), 3.98 (2H, t), 3.87-3.74 (3H, m), 3.68-3.57(2H, m), 3.52-3.46 (1H, m), 3.40-3.34 (1H, m), 2.91 (2H, t)

Intermediate 82-([1,4]dioxan-2-ylmethoxy)-9-hydroxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Intermediate 8 was prepared using general method B starting fromcompound 1. (¹H, DMSO-d6) δ (ppm): 7.84 (1H, d), 6.77 (1H, dd), 6.74(1H, d), 6.45 (1H, s), 4.27-4.20 (2H, m); 3.99 (2H, t), 3.88-3.73 (3H,m), 3.68-3.58 (2H, m), 3.52-3.46 (1H, m), 3.40-3.34 (1H, m), 2.91 (2H,t)

MW (calcd): 330.4; MW (obsd): 331.0 (M+1)

General Method C

A solution of intermediate 6, 7 or 8 (1 eq.),N-phenyl-bis(trifluoromethanesulfonimide) (1.2 eq.) and Et₃N (1.3 eq.)in DCM under nitrogen is stirred at RT until completion. The reactionmixture is concentrated and the crude is purified by crystallizationfrom iPrOH to afford intermediate 9, 10 or 11.

Illustrative Synthesis of General Method C Intermediate 9Trifluoro-methanesulfonic acid2-((S)-1-[1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-ylester

A solution of intermediate 6, (24 g, 72.7 mmol, 1 eq.),N-phenyl-bis(trifluoromethanesulfonimide) (31.15 g, 87.2 mmol, 1.2 eq.)and Et₃N (13.2 mL, 94.4 mmol, 1.3 eq.) in DCM (700 mL) under a nitrogenatmosphere is stirred at RT overnight. The reaction mixture isconcentrated. The crude is taken in iPrOH (75 mL) heated under refluxand cool to RT. After two days at RT, the solid is filtered off anddried to afford intermediate 9.

(¹H, CDCl₃) δ (ppm): 7.83 (1H, d), 7.35 (1H, dd), 7.29 (1H, d), 6.41(1H, s), 4.51-4.42 (2H, m), 4.28 (2H, t), 4.06-4.01 (1H, m), 3.89-3.69(5H, m), 3.52 (1H, m), 3.11 (2H, t)

Intermediate 10 Trifluoro-methanesulfonic acid2-((R)-1-[1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-ylester

Intermediate 10 was prepared using general method C starting fromintermediate 7.

(¹H, CDCl₃) δ (ppm): 7.83 (1H, d), 7.34 (1H, dd), 7.29 (1H, d), 6.41(1H, s), 4.51-4.41 (2H, m), 4.28 (2H, t), 4.05-4.00 (1H, m), 3.91-3.66(5H, m), 3.52 (1H, t), 3.11 (2H, t)

Intermediate 11 Trifluoro-methanesulfonic acid2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-ylester

Intermediate 11 was prepared using general method C starting fromintermediate 8.

(¹H, DMSO-d6) δ (ppm): 8.21 (1H, d), 7.65 (1H, d), 7.54 (1H, dd), 6.75(1H, s), 4.28-4.26 (2H, m), 4.04 (2H, t), 3.90-3.84 (1H, m), 3.81-3.75(2H, m), 3.68-3.58 (2H, m), 3.53-3.47 (1H, m), 3.41-3.36 (1H, m), 3.10(t, 2H)

MW (calcd): 462.4; MW (obsd): 463.3 (M+1)

Intermediate 139-amino-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-onehydrochloride Step 1:9-(Benzhydrylidene-amino)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 12)

A solution of intermediate 9 (1 g, 2.16 mmol, 1 eq.), Pd(OAc)₂ (24 mg,0.11 mmol 0.05 eq.), Cs₂CO₃ (2.11 g, 6.48 mmol, 3 eq.) BINAP (134 mg,0.21 mmol, 0.1 eq.) and benzophenonimine (587 mg, 3.24 mmol, 1.5 eq.) intoluene (20 mL) was heated at 150° C. in a microwave for 45 min. Thesolvent was evaporated to dryness and the crude mixture was taken inwater and extracted with EtOAc. The organic layer was dried over MgSO₄and concentrated under vacuum.9-(Benzhydrylidene-amino)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-oneintermediate 12 was obtained after purification by flash chromatographyon silica gel and immediately used in next step.

Step 2:9-amino-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-onehydrochloride (Intermediate 13)

To a solution of intermediate 12 in a minimum of DCM/Et₂O was added HCl2N in Et₂O (4 mL). The precipitate was filtered off and dried to affordintermediate 13.

(¹H, DMSO-d6) δ (ppm): 7.82 (1H, d), 7.45 (3H, br), 6.68 (1H, d), 6.67(1H, s), 6.51 (1H, s), 4.32 (2H, d), 3.99 (2H, t), 3.90-3.84 (1H, m),3.82-3.35 (6H, m), 2.88 (2H, t)

MW (calcd): 329.4; MW (obsd): 330.2 (M+1)

General Method D

The corresponding alcohol (2 eq.) is added to a solution of NaH (2 eq.,60% in mineral oil) in THF at 0° C. The reaction is warmed to RT for 30min then cooled again at 0° C. Bromo methyltrifluoroborate (1 eq.) isadded to the reaction in one portion and the mixture is stirred at RTfrom few hours to 3 days (monitoring by ¹⁹F-NMR). The reaction isquenched with a solution of KHF₂ (1.5 M, 3 eq.) and the mixture isevaporated to dryness. The residue is suspended in acetone, theinorganics are filtered off and the filtrate is evaporated to dryness.The residue is suspended in a minimum amount of acetone, Et₂O is addedand the product is obtained by filtration.

Illustrative Synthesis of General Method D Intermediate 14Tetrahydro-2H-pyran-4-ol-methyl trifluoroborate

Tetrahydro-pyran-4-ol (152 mg, 1.49 mmol, 2 eq.) was added to a solutionof NaH (60 mg, 1.49 mmol, 2 eq., 60% in mineral oil) in THF (4 mL) at 0°C. The reaction was warmed to RT for 30 min then cooled again at 0° C.Bromo methyltrifluoroborate (150 mg, 0.75 mmol, 1 eq.) was added to thereaction in one portion and the mixture was stirred at RT for 1 day(monitoring by ¹⁹F-NMR). The reaction was quenched with a solution ofKHF₂ (1.5 mL, 1.5 M, 3 eq.) and the mixture was evaporated to dryness.The residue was suspended in acetone, the inorganics were filtered offand the filtrate was evaporated to dryness. The residue was suspended ina minimum amount of acetone (1.5 mL), and Et₂O (6 mL) was added.Intermediate 14 was obtained by filtration.

(¹H, DMSO-d₆) δ ppm 3.78 (2 H, d), 3.31-3.21 (2 H, m), 3.18-3.08 (1 H,m), 2.50-2.45 (2 H, m), 1.86-1.74 (2 H, m), 1.34-1.19 (2 H, m)

Intermediate 15 Potassium 3-oxy-oxetanemethyltrifluoroborate

Intermediate 15 was prepared via general method D with oxetan-3-ol (thetrifluoroborate reagent was recovered with the inorganics rather thanthe filtrate).

(¹H, DMSO-d₆) δ ppm 4.56 (2 H, s), 4.32 (3 H, d), 2.40 (2 H, d)

Intermediate 16 Potassium(3-methyl-3-methyloxy-oxetane-methyltrifluoroborate

Intermediate 16 was prepared via general method D with(3-methyloxetan-3-yl)methanol (the trifluoroborate reagent was recoveredwith the inorganics rather than the filtrate).

(¹H, DMSO-d₆) δ ppm 4.34 (2 H, d), 4.14 (2 H, d), 3.26 (2 H, s),2.59-2.52 (2 H, m), 1.19 (3 H, s)

Intermediate 17 Potassium 2,2-dimethyl-propyloxy-methyltrifluoroborate

Intermediate 17 was prepared via general method D with2,2-dimethyl-propan-1-ol.

(¹H, DMSO-d₆) δ ppm 2.88 (2 H, s), 2.51-2.45 (2H, m), 0.83 (9 H, s)

Intermediate 18 Potassium cyclopropylmethoxy-methyltrifluoroborate

Intermediate 18 was prepared via general method D withcyclopropyl-methanol.

(¹H, DMSO-d₆) δ ppm 3.00 (2 H, d), 2.46 (2 H, d), 1.00-0.82 (1 H, m),0.46-0.31 (2 H, m), 0.13-0.00 (2 H, m)

Intermediate 19 Cyclopentylmethoxy-methyltrifluoroborate

Intermediate 19 was prepared via general method D withcyclopentyl-methanol.

(¹H, DMSO-d₆) δ ppm 3.04 (2 H, d), 2.46 (2 H, d), 2.08-1.94 (1 H, m),1.47 (6 H, br. s.), 1.07-1.22 (2 H, m)

Intermediate 20 Potassium 2-cyclopropyl-ethyl-trifluoroborate

A 2-neck round bottom flask equipped with a reflux condenser and anaddition funnel was charged with Mg (193 mg, 8.05 mmol, 3 eq.) and Et₂O(1 mL) under N₂. One drop of neat (2-bromo-ethyl)-cyclopropane was addedfollowed by two drops of dibromoethane. Once the 1^(st) bubblesappeared, (2-bromo-ethyl)-cyclopropane (400 mg, 2.68 mmol, 1 eq.) inEt₂O (5 mL) was added dropwise. Upon completion of the addition, theresulting suspension was stirred at RT for 1 h. In a separate flask,purged with N₂, a solution made of B(OMe)₃ (0.45 mL, 4.02 mmol, 1.5 eq.)in THF (6 mL) was cooled to −78° C. To this solution, the2-cyclopropyl-ethyl magnesium bromide suspension was added dropwise viaa double ended needle. The mixture was allowed to stir for 1 h at −78°C. and then was warmed to RT for 1 h. After cooling the mixture to 0°C., a saturated aqueous solution of KHF₂ (2.5 mL, 4.5 M, 4.1 eq.) wasadded dropwise and the reaction mixture was allowed to warm to RT. After30 min, the solution was concentrated in-vacuo. The dried solids weretriturated with hot acetone and filtered to remove inorganic salts. Theresulting filtrate was concentrated and the solid residue was trituratedwith Et₂O. Potassium 2-cyclopropyl-ethyl-trifluoroborate was filteredand dried in-vacuo.

(¹H, DMSO-d₆) δ ppm 1.07-0.92 (2 H, m), 0.66-0.53 (1 H, m), 0.27-0.21 (2H, m), 0.067-−0.07 (2 H, m), −0.117-−0.17 (2 H, m)

General Method E

A vial is charged with intermediate 9, 10 or 11 (1 eq.), the appropriateboronic acid, boronic ester or potassium trifluoroborate (4.4 eq.),Cs₂CO₃ (2.6 eq.), (DPPF)PdCl₂.DCM (0.05 eq.), in 1,4-dioxane/H₂O (10/1,v/v), and the mixture is degassed with N₂. The vial is sealed and heatedat 80° C. When the reaction is complete, the vial is cooled to RT andthe reaction is either worked up or volatiles are evaporated undervacuum. The product is then obtained after purification by either flashchromatography on silica gel, preparative TLC or preparative HPLC-MS.

Illustrative Synthesis of General Method E Compound 22-([1,4]dioxan-2-ylmethoxy)-9-pyridin-3-yl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

A vial was charged with intermediate 11 (84 mg, 0.074 mmol, 1 eq.),pyridine-3-boronic acid (40 mg, 0.327 mmol, 4.4 eq.), Cs₂CO₃ (62 mg,0.190 mmol, 2.6 eq.), (DPPF)PdCl₂.DCM (3.3 mg, 0.004 mmol, 0.05 eq.), in1,4-dioxane (1 mL) and H₂O (0.1 mL), and the mixture was degassed withN₂. The vial was sealed and heated at 80° C. After 1 h, the vial wascooled to RT and volatiles were evaporated under vacuum. The residue wasthen purified by flash chromatography on silica gel, eluting with 7.5%MeOH/DCM to afford compound 2.

(¹H, CDCl₃) δ ppm 8.89 (1 H, s), 8.67 (1 H, d), 7.93 (1 H, d), 7.82 (1H, d), 7.61 (1 H, d), 7.53 (1 H, s), 7.43 (1 H, dd), 6.43 (1 H, s),4.51-4.37 (2 H, m), 4.26 (2 H, t), 3.99 (1 H, m), 3.92-3.60 (5 H, m),3.49 (1 H, m), 3.10 (2 H, t)

General Method F

A solution of intermediate 6, 7, or 8 (1 eq.), the appropriatealkylating agent (1.5 eq.), K₂CO₃ (2 eq.), KI (1 eq.) in MEK is heatedat 80° C. When the reaction is complete, the volatiles are evaporated todryness and the residue is purified by flash chromatography on silicagel to give the desired product.

Illustrative Synthesis of General Method F Compound 82-([1,4]dioxan-2-ylmethoxy)-9-(oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

A solution of intermediate 8 (40 mg, 0.12 mmol, 1 eq.),2-chloromethyloxazole (21 mg, 0.18 mmol, 1.5 eq.), K₂CO₃ (33 mg, 0.24mmol, 2 eq.), KI (20 mg, 0.12 mmol, 1 eq.) in MEK (2 mL) was heated at80° C. for 16 h. The reaction was evaporated to dryness and the residuewas purified by flash chromatography on silica gel, eluting with 4%MeOH/DCM to give compound 8.

(¹H, CDCl₃) δ ppm 7.72 (1 H , d), 7.68-7.60 (1 H , m), 7.18 (1 H , d),7.02 (1 H , dd), 6.93 (1 H , d), 6.28 (1 H , s), 5.23 (2 H , s),4.49-4.33 (2 H , m), 4.19 (2 H , t), 4.02-3.94 (1 H , m), 3.89-3.61 (5 H, m), 3.48 (1 H , dd), 2.98 (2 H , t)

MW (calcd): 411.4; MW (obsd): 412.4 (M+1)

General Method G

Intermediate 9, 10, 11 (1 eq.) is dissolved in DMF, the appropriatealkyne (3 eq.) is added followed by TEA (3.5 eq.), and the mixture isdegassed. Pd(PPh₃)₃Cl₂ (0.05 eq.) is added with CuI (0.2 eq.) and thereaction mixture is heated at 80° C. When the reaction is gone tocompletion, it is cooled to RT and either worked up or volatiles areevaporated to dryness. The product is then obtained after purificationby either flash chromatography on silica gel, preparative TLC orpreparative HPLC-MS.

Illustrative Synthesis of General Method G Compound 162-([1,4]dioxan-2-ylmethoxy)-9-(1-methyl-1H-imidazol-2-ylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Intermediate 11 (1.4 g, 3.03 mmol, 1 eq.) was dissolved in DMF (20 mL),5-ethynyl-1-methyl-1H-imidazole (0.92 mL, 9.09 mmol, 3 eq.) was addedfollowed by TEA (1.48 mL, 10.61 mmol, 3.5 eq.). The mixture was degassedand Pd(PPh₃)₃Cl₂ (106 mg, 0.15 mmol, 0.05 eq.) was added with CuI (115mg, 0.61 mmol, 0.2 eq.). The reaction mixture was heated at 80° C. for16 h. The reaction was cooled to RT and quenched with brine, the mixturewas then extracted with EtOAc. The organic layer was dried over MgSO₄and the solvent was evaporated under vacuum. The crude product was thenpurified by flash chromatography on silica gel, eluting from 0 to 5%MeOH/DCM to give compound 16.

(¹H, CDCl₃) δ ppm 7.73 (1 H , d), 7.57-7.50 (2 H , m), 7.48-7.45 (1 H ,m), 7.42 (1 H , d), 6.42 (1 H , s), 4.53-4.39 (2 H , m), 4.28-4.23 (2 H, m), 4.07-3.97 (1 H , m), 3.94-3.64 (8 H , m), 3.52 (1 H , dd), 3.06 (2H , t)

MW (calcd): 418.4; MW (obsd): 419.4 (M+1)

General Method H

tBuOK (3 eq.) is added to a solution of the corresponding acetylenicalcohol (1 eq.) in THF, MeI (10 eq.) is then added and the reaction isstirred at RT. When the reaction has gone to completion, the reactionmixture is filtered and the filtrate is evaporated to dryness. Productis obtained after purification by preparative TLC.

Illustrative Synthesis of General Method H Compound 1102-([1,4]dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

tBuOK (5.19 mg, 0.046 mmol, 0.95 eq.) was added to a solution ofcompound 90 (20 mg, 0.049 mmol, 1 eq.) in THF (2 mL), MeI (0.030 mL,0.487 mmol, 10 eq.) was then added and the reaction was stirred at RTfor 16 h. Some more tBuOK (11 mg, 0.097 mmol, 2 eq.) was added and thereaction was stirred for an extra day. The reaction mixture was filteredand the filtrate was evaporated to dryness. The crude product waspurified by preparative TLC eluting with 2% MeOH/DCM to yield compound110.

(¹H, CDCl₃) δ ppm 7.70-7.60 (1 H , d), 7.50-7.42 (1 H , d), 7.39 (1 H ,s), 6.37 (1 H , s), 4.50-4.35 (2 H , m), 4.25-4.15 (2 H , m), 4.05-3.95(2 H , m), 3.92-3.60 (5 H , m), 3.56-3.45 (4 H , m), 3.05-3.95 (2 H ,m), 2.15-1.95 (1 H , m), 1.15-1 (6 H , t)

MW (calcd): 424.5; MW (obsd): 425.2 (M+1)

General Method I

A vial is charged with Pd/C (10% w/w) and a solution of the appropriatealkyne (1 eq.) in MeOH is added. The system is purged with N₂ beforebeing filled with H₂ then the reaction is stirred at RT untilcompletion. The reaction is filtered through Celite and the filtrate isevaporated to dryness. Clean product is obtained after purification byeither flash chromatography on silica gel, preparative TLC orpreparative HPLC-MS.

Illustrative Synthesis of General Method I Compound 1162-([1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-propyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

A vial was charged with Pd/C (9 mg, 10% w/w) and a solution of compound108 (87 mg 0.20 mmol, 1 eq.) in MeOH (10 mL) was added. The system waspurged with N₂ before being filled with H₂ then the reaction was stirredfor 16 h at RT. The reaction was filtered through Celite and thefiltrate was evaporated to dryness. The crude product was purified bypreparative HPLC-MS to give compound 116.

(¹H, CDCl₃) δ ppm 8.60-8.48 (2 H , m), 7.73 (1 H , d), 7.61 (1 H , d),7.30 (1 H , dd), 7.20 (1 H , d), 7.12 (1 H , s), 6.35 (1 H , s), 4.77 (1H , dd), 4.47-4.33 (2 H , m), 4.18 (2 H , t), 3.97 (1 H , m), 3.90-3.60(5 H , m), 3.48 (1 H , t), 2.96 (2 H , t), 2.90-2.70 (2 H , m), 2.15 (1H , m), 2.10-1.98 (1 H , m), 1.38 (1 H , t) MW (calcd): 449.5; MW(obsd): 450.1 (M+1)

General Method J

Intermediate 13 (1 eq.) is dissolved in DMF, the appropriate aldehyde (4eq.) is added followed by KOH (1 eq.). The reaction is stirred for 15min at RT before STAB (10 eq.) is added, the mixture is then stirred atRT until completion of the reaction. The mixture is then quenched withbrine, extracted with EtOAc, the organic layer is dried over MgSO₄ andevaporated to dryness. Purification by preparative HPLC-MS affords thecorresponding product.

Illustrative Synthesis of General Method J Compound 1269-(2,2-dimethyl-butylamino)-2-(S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Intermediate 13 (50 mg, 0.14 mmol, 1 eq.) was dissolved in DMF (2 mL),2,2-dimethylbutanal (56 mg, 0.56 mmol, 4 eq.) was added followed by KOH(8 mg, 0.14 mmol, 1 eq.). The reaction was stirred for 15 min at RTbefore STAB (297 mg, 1.40 mmol, 10 eq.) was added, the mixture was thenstirred for 2 days at RT. The reaction was quenched with brine and themixture was extracted with EtOAc. The organic layer was dried over MgSO₄and evaporated to dryness. The crude product was purified by preparativeHPLC-MS to give compound 126.

(¹H, CDCl₃) δ ppm 7.50 (1 H , d), 6.63 (1 H , dd), 6.48 (1 H , s), 6.21(1 H , s), 4.47-4.34 (2 H , m), 4.21-4.14 (2 H , m), 4.01-3.91 (1 H ,m), 3.89-3.60 (5 H , m), 3.48 (1 H , dd), 2.98 (2 H , s), 2.90 (2 H ,t), 1.36 (2 H , dd), 0.96 (6 H , s), 0.87 (3 H , t)

MW (calcd): 413.5; MW (obsd): 414.4 (M+1)

General Method K

Step 1:2((S)-1-[1,4]-dioxan-2-ylmethoxy)-9-(3-hydroxy-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 15)

Intermediate 152-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-onewas synthesised via general method E with intermediate 9 andprop-2-yn-1-ol.

Step 2

Intermediate 15 (1 eq.) is dissolved in a mixture of THF/DMF (1/1), NaH(1.1 eq., 60% in mineral oil) is added followed by the appropriatealkylating agent (1 eq.) and the reaction is stirred at 70° C. When thereaction has gone to completion, the mixture is worked up with brine andEtOAc, the organic layer is dried over MgSO₄ and evaporated to dryness.Purification by preparative HPLC-MS provides the corresponding product.

Illustrative Synthesis of General Method K Compound 1332-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-[3-(2-methoxy-ethoxy)-prop-1-ynyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Intermediate 15 (92 mg, 0.25 mmol, 1 eq.) was dissolved in a mixture ofTHF/DMF (6 mL, 1/1), NaH (11 mg, 0.275 mmol, 1.1 eq., 60% in mineraloil) was added followed by 1-bromo-2-methoxy-ethane (35 mg, 0.25 mmol, 1eq.) and the reaction was stirred at RT for 16 h, then at 70° C. for 1day. The mixture was worked up with brine and EtOAc, the organic layerwas dried over MgSO₄ and evaporated to dryness. The crude product waspurified by preparative HPLC-MS to provide compound 133.

(¹H, CDCl₃) δ ppm 7.64 (1 H , s), 7.48-7.40 (1 H , m), 7.40-7.35 (1 H ,m), 6.40-6.34 (1 H , m), 4.47 (4 H , s), 4.28-4.15 (1 H , m), 3.93-3.56(10 H , m), 3.43 (5 H , s), 3.06-2.95 (2 H , m) MW (calcd): 426.5; MW(obsd): 427.4 (M+1)

General Method L

To a solution of tBuOK (2.2 eq.) in DMF is added dropwise a solution ofintermediate 6 (1 eq.) in DMF at 0° C. and the mixture is stirred for 1h. A solution of the appropriate alkylating agent (10 eq.) in DMF isadded dropwise to the previous solution at 0° C., then the reaction isstirred at 80° C. When the reaction has gone to completion, the mixtureis cooled to RT, quenched with water, and extracted with EtOAc. Thecombined organic layers are dried over Na₂SO₄ and evaporated to dryness.The product is isolated by purification by preparative TLC.

Illustrative Synthesis of General Method L Compound 1589-(2,2-dimethyl-propoxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

To a solution of tBuOK (19 mg, 0.166 mmol, 1.1 eq.) in DMF (2 mL) wasadded dropwise a solution of intermediate 6 (50 mg, 0.151 mmol, 1 eq.)in DMF (2 mL) at 0° C. and the mixture was stirred for 1 h. A solutionof 1-iodo-2,2-dimethyl-propane (0.021 mL, 0.159 mmol, 1.05 eq.) in DMF(2 mL) was added dropwise to the previous solution at 0° C., then thereaction was stirred at 80° C. for 1 day. Extra reagents were added,1-iodo-2,2-dimethyl-propane (0.4 mL, 10 eq.) and tBuOK (19 mg, 0.166mmol, 1.1 eq.) and the reaction was stirred at 80° C. for one more day.The mixture was cooled to RT, quenched with water, and extracted withEtOAc. The combined organic layers were washed with brine, dried overNa₂SO₄ and evaporated to dryness. Compound 158 was obtained bypurification by preparative TLC [DCM/MeOH, 98/2]. (¹H, CDCl₃) δ ppm7.70-7.56 (1 H , d), 6.95-6.85 (1 H , d), 6.80 (1 H , s), 6.28 (1 H ,s), 4.50-4.35 (2 H , m), 4.25-4.10 (2 H , m), 4.05-3.92 (1 H , m),3.10-3.57 (8 H , m), 3.55-3.40 (1 H , m), 3.05-2.90 (2 H , m), 1.05 (9H, s).

MW (calcd): 400.5; MW (obsd): 401.2 (M+1)

Compounds of the Invention

The compounds according to the invention can be produced as describedbelow.

Compound 19-Allyloxy-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Synthesis fully described above.

Compound 22-([1,4]dioxan-2-ylmethoxy)-9-pyridin-3-yl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Synthesis fully described above.

Compound 32-([1,4]dioxan-2-ylmethoxy)-9-pyridin-4-yl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 andpyridine-4-boronic acid.

Compound 42-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile

This compound is prepared via general method E using intermediate 11 and2-cyanophenylboronic acid.

Compound 53-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile

This compound is prepared via general method E using intermediate 11 and3-cyanophenylboronic acid.

Compound 64-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile

This compound is prepared via general method E using intermediate 11 and4-cyanophenylboronic acid.

Compound 7[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile

This compound is prepared via general method F using intermediate 8 andbromo-acetonitrile, KI was not used in the experiment.

Compound 82-([1,4]dioxan-2-ylmethoxy)-9-(oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Synthesis fully described above.

Compound 92-([1,4]dioxan-2-ylmethoxy)-9-(pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 8 andpyridin-2-yl-methanol hydrochloride.

Compound 109-(3,5-dichloro-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and3,5-dichlorophenylboronic acid.

Compound 119-benzofuran-2-yl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and1-benzofuran-2-ylboronic acid.

Compound 122-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-indole-1-carboxylicacid tert-butyl ester

This compound is prepared via general method E using intermediate 11 and1-(tert-butoxycarbonyl)-1H-indol-2-ylboronic acid.

Compound 132-([1,4]dioxan-2-ylmethoxy)-9-(1H-indol-2-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Compound 12 (57 mg, 0.11 mmol) was dissolved in a mixture of DCM/TFA(1/1, 2 mL) and the reaction was stirred at RT for 6 h. The mixture wasevaporated to dryness to recover compound 13 as a TFA salt.

(¹H DMSO-d₆) δ ppm 8.11 (1 H , d), 7.95-7.86 (2 H , m), 7.57 (1 H , d),7.43 (1 H , d), 7.15 (1 H , t), 7.10 (1 H , d), 6.71 (1 H , s),4.31-4.25 (2 H , m), 4.09 (2 H , t), 3.92-3.84 (1 H , m), 3.79 (2 H ,td), 3.71-3.57 (2 H , m), 3.55-3.46 (1 H , m), 3.40 (1 H , dd), 3.08 (2H , t)

MW (calcd): 429.5 MW (obsd): 430.5 (M+1)

Compound 142-([1,4]dioxan-2-ylmethoxy)-9-(6-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and2-methoxy-5-pyridineboronic acid.

Compound 152-([1,4]dioxan-2-ylmethoxy)-9-(6-trifluoromethyl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and2-(trifluoromethyl)pyridine-5-boronic acid.

Compound 162-([1,4]dioxan-2-ylmethoxy)-9-(3-methyl-3H-imidazol-4-ylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Synthesis fully described above.

Compound 179-(5-tert-butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 8 and5-(tert-butyl)-3-(chloromethyl)-1,2,4-oxadiazole.

Compound 185-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine-2-carboxylicacid methylamide

This compound is prepared via general method E using intermediate 11 and2-(N-methylaminocarbonyl)pyridine-5-boronic acid pinacol ester.

Compound 192-([1,4]dioxan-2-ylmethoxy)-9-pent-1-ynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 andpent-1-yne.

Compound 202-([1,4]dioxan-2-ylmethoxy)-9-(2-pyridin-2-yl-ethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-([1,4]dioxan-2-ylmethoxy)-9-((E)-2-pyridin-2-yl-vinyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(intermediate 22)

A round bottom flask was charged with intermediate 11 (50 mg, 0.11 mmol,1 eq.), 2-vinyl-pyridine (0.014 mL, 0.13 mmol, 1.2 eq.), (DPPF)PdCl₂.DCM(4.4 mg, 0.0054 mmol, 0.05 eq.) and TEA (0.03 mL, 0.22 mmol, 2 eq.)under N₂ then the flask was degassed. DMF (2 mL) was then added and thereaction was stirred at 100° C. for 16 h. The reaction was cooled to RTand evaporated to dryness, the residue was then purified by flashchromatography on silica gel, eluting from 0 to 3% MeOH/DCM affordingintermediate 222-([1,4]dioxan-2-ylmethoxy)-9-(E)-2-pyridin-2-yl-vinyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one.

(¹H, CDCl₃) δ ppm 8.66-8.59 (1 H , m), 7.74-7.53 (4 H , m), 7.46 (1 H ,s), 7.39 (1 H , d), 7.30-7.15 (2 H , m), 6.37 (1 H , s), 4.48-4.34 (2 H, m), 4.21 (2 H , t), 4.02-3.93 (1 H , m), 3.89-3.59 (5 H , m),3.53-3.42 (1 H, m), 3.03 (2 H , m)

MW (calcd): 417.5; MW (obsd): 418.4 (M+1)

Step 2:2-([1,4]dioxan-2-ylmethoxy)-9-(2-pyridin-2-yl-ethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 20)

A round bottom flask was charged with intermediate 22 (45 mg, 0.11 mmol,1 eq.), PtO₂ (6 mg, 0.025 mmol, 0.23 eq.) and THF (2 mL) was added. Thesystem was purged with N₂ before being filled with H₂ then the reactionwas stirred for 16 h at RT. The reaction mixture was filtered through aSPE guanidine cartridge and the solvent was evaporated to dryness. Thecrude product was purified by flash chromatography on silica gel,eluting from 1 to 10% MeOH/DCM to give compound 20.

(¹H, CDCl₃) δ ppm 8.58 (1 H , dd), 7.66-7.56 (2 H , m), 7.22 (1 H , dd),7.19-7.09 (3 H , m), 6.36 (1 H , s), 4.50-4.36 (2 H , m), 4.25-4.17 (2 H, m), 4.04-3.95 (1 H , m), 3.91-3.62 (5 H , m), 3.50 (1 H , dd), 3.14 (4H, s), 2.98 (2 H , t)

MW (calcd): 419.5; MW (obsd): 420.5 (M+1)

Compound 212-([1,4]dioxan-2-ylmethoxy)-9-(2-pyrazin-2-yl-ethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-([1,4]dioxan-2-ylmethoxy)-9-((E)-2-pyrazin-2-yl-vinyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(intermediate 23)

A round bottom flask was charged with intermediate 11 (50 mg, 0.11 mmol,1 eq.), 2-vinyl-pyridine (0.014 mL, 0.13 mmol, 1.2 eq.), (DPPF)PdCl₂.DCM(4.4 mg, 0.0054 mmol, 0.05 eq.) and TEA (0.03 mL, 0.22 mmol, 2 eq.)under N₂ then the flask was degassed. DMF (2 mL) was then added and thereaction was stirred at 100° C. for 16 h. The reaction was cooled to RTand evaporated to dryness, the residue was then purified by flashchromatography on silica gel, eluting from 0 to 4% MeOH/DCM affordingintermediate 232-([1,4]dioxan-2-ylmethoxy)-9-(E)-2-pyrazin-2-yl-vinyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one.

(¹H, CDCl₃) δ ppm 8.69 (1 H , m), 8.63-8.58 (1 H , m), 8.49 (1 H , m),7.84-7.71 (2 H , m), 7.63 (1 H , d), 7.53 (1 H , s), 7.31 (1 H , s),6.42 (1 H , s), 4.52-4.39 (2 H , m), 4.30-4.22 (2 H , m), 4.02 (1 H ,dd), 3.93-3.63 (5 H , m), 3.52 (1 H , dd), 3.08 (2 H , m)

MW (calcd): 418.5; MW (obsd): 419.4 (M+1)

Step 2:2-([7,4]dioxan-2-ylmethoxy)-9-(2-pyrazin-2-yl-ethyl)-6,7-dihydro-pyrimido[6,1-c]isoquinolin-4-one(Compound 21)

A round bottom flask was charged with intermediate 23 (38 mg, 0.09 mmol,1 eq.), PtO₂ (5 mg, 0.021 mmol, 0.23 eq.) and THF (2 mL) was added. Thesystem was purged with N₂ before being filled with H₂ then the reactionwas stirred for 16 h at RT. The reaction mixture was filtered through aSPE guanidine cartridge and the solvent was evaporated to dryness. Thecrude product was purified by flash chromatography on silica gel,eluting from 1 to 10% MeOH/DCM to give compound 21.

(¹H, CDCl₃) δ ppm 8.55 (1 H , dd), 8.44 (2 H , dd), 7.63 (1 H , d), 7.22(1 H , dd), 7.15 (1 H , s), 6.36 (1 H , s), 4.36-4.53 (2 H , m),4.17-4.26 (2 H , m), 3.95-4.07 (1 H , m), 3.61-3.93 (5 H , m), 3.51 (1 H, dd), 3.17 (4H, s), 2.99 (2 H , t)

MW (calcd): 420.5; MW (obsd): 421.5 (M+1)

Compound 222-([1,4]dioxan-2-ylmethoxy)-9-(1H-indol-5-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E intermediate 11 and using5-indolylboronic acid.

Compound 232-([1,4]dioxan-2-ylmethoxy)-9-(2-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and2-methoxyphenylboronic acid.

Compound 242-([1,4]dioxan-2-ylmethoxy)-9-(5-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and3-methoxy-5-pyridineboronic acid pinacol ester.

Compound 252-([1,4]dioxan-2-ylmethoxy)-9-(1H-indazol-5-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and1H-indazole-5-boronic acid.

Compound 262-([1,4]dioxan-2-ylmethoxy)-9-(4-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and4-methoxyphenylboronic acid.

Compound 273-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzamide

This compound is prepared via general method E using intermediate 11 and3-aminocarbonyphenylboronic acid.

Compound 285-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-2-fluoro-benzamide

This compound is prepared via general method E using intermediate 11 and3-(aminocarbonyl)-4-fluorobenzeneboronic acid.

Compound 29N-{3-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-phenyl}-acetamide

This compound is prepared via general method E intermediate 11 and using3-acetamidophenylboronic acid.

Compound 309-cyclopropylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G intermediate 11 and usingethynyl-cyclopropane.

Compound 312-([1,4]dioxan-2-ylmethoxy)-9-(1-hydroxy-cyclopentylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G intermediate 11 and using1-ethynyl-cyclopentanol.

Compound 322-([1,4]dioxan-2-ylmethoxy)-9-pyrimidin-5-yl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E intermediate 11 and using5-pyrimidinylboronic acid.

Compound 339-cyclohex-1-enyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 andcyclohexene-1-boronic acid pinacol ester.

Compound 342-([1,4]dioxan-2-ylmethoxy)-9-(1-methyl-1H-indol-5-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and1-methylindole-5-boronic acid pinacol ester.

Compound 352-([1,4]dioxan-2-ylmethoxy)-9-(6-methyl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and6-methylpyridin-3-ylboronic acid.

Compound 362-([1,4]dioxan-2-ylmethoxy)-9-pyridin-2-ylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 and2-ethynyl-pyridine.

Compound 372-([1,4]dioxan-2-ylmethoxy)-9-(3-methoxy-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 and3-methoxy-propyne.

Compound 385-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pent-4-ynenitrile

This compound is prepared via general method G using intermediate 11 andpent-4-ynenitrile.

Compound 392-([1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 andprop-2-yn-1-ol.

Compound 402-([1,4]dioxan-2-ylmethoxy)-9-(4-methoxy-phenylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 and1-ethynyl-4-methoxy-benzene.

Compound 412-([1,4]dioxan-2-ylmethoxy)-9-pyridin-3-ylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 and3-ethynyl-pyridine

Compound 424-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-N-methyl-benzamide

This compound is prepared via general method E using intermediate 11 and4-(N-methylaminocarbonyl)phenylboronic acid.

Compound 432-([1,4]dioxan-2-ylmethoxy)-9-(3-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and3-methoxyphenylboronic acid.

Compound 449-(2-chloro-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and2-chlorophenylboronic acid.

Compound 452-([1,4]dioxan-2-ylmethoxy)-9-(4-hydroxy-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 andbut-3-yn-1-ol.

Compound 469-(1,5-dimethyl-1H-pyrazol-3-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 8 and3-chloromethyl-1,5-dimethyl-1H-pyrazole.

Compound 472-([1,4]dioxan-2-ylmethoxy)-9-(1-methyl-1H-pyrazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 8 and3-chloromethyl-1-methyl-1H-pyrazole.

Compound 482-([1,4]dioxan-2-ylmethoxy)-9-(3-methyl-[1,2,4]oxadiazol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 8 and5-chloromethyl-3-methyl-[1,2,4]oxadiazole.

Compound 492-([1,4]dioxan-2-ylmethoxy)-9-(4-morpholin-4-yl-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and4-morpholinophenylboronic acid, with CsF as base and DMF as solvent.

Compound 503-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-4-fluoro-benzamide

This compound is prepared via general method E using intermediate 11 and5-carbamoyl-2-fluorobenzeneboronic acid, with CsF as base and DMF assolvent.

Compound 513-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-5-fluoro-benzamide

This compound is prepared via general method E using intermediate 11 and3-(aminocarbonyl)-5-fluorobenzeneboronic acid, with CsF as base and DMFas solvent.

Compound 529-(3,3-Dimethyl-but-1-ynyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 and3,3-dimethyl-but-1-yne.

Compound 532-([1,4]dioxan-2-ylmethoxy)-9-pyridin-4-ylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 and4-ethynyl-pyridine.

Compound 542-([1,4]dioxan-2-ylmethoxy)-9-(3-methyl-isoxazol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 8 and5-chloromethyl-3-methyl-isoxazole.

Compound 552-([1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 and2-methyl-but-3-yn-2-ol.

Compound 562-([1,4]dioxan-2-ylmethoxy)-9-(2-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and2-methoxy-3-pyridinyl boronic acid.

Compound 572-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 andpotassium (cyanomethyl) trifluoroborate.

Compound 589-(3,6-dihydro-2H-pyran-4-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and3,6-dihydro-2H-pyran-4-boronic acid pinacol ester.

Compound 595-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine-2-carbonitrile

This compound is prepared via general method E using intermediate 11 and2-cyanopyridine-5-boronic acid pinacol ester.

Compound 602-([1,4]Dioxan-2-ylmethoxy)-9-(6-isopropoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and6-isopropoxypyridine-3-boronicacid pinacol ester.

Compound 612-([1,4]dioxan-2-ylmethoxy)-9-(6-ethoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and6-ethoxypyridine-3-boronic acid.

Compound 622-([1,4]dioxan-2-ylmethoxy)-9-(6-morpholin-4-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]morpholine.

Compound 639-(2,3-dimethoxy-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and2,3-dimethoxyphenylboronic acid.

Compound 649-(3-chloro-2-methoxy-pyridin-4-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and3-chloro-2-methoxypyridine-4-boronic acid.

Compound 652-([1,4]dioxan-2-ylmethoxy)-9-(2-methyl-pyridin-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and2-methylpyridine-4-boronic acid pinacol ester.

Compound 663-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-isonicotinonitrile

This compound is prepared via general method E using intermediate 11 and4-cyanopyridine-3-boronic acid pinacol ester.

Compound 679-(2,5-dimethoxy-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and2,5-dimethoxyphenylboronic acid.

Compound 682-([1,4]dioxan-2-ylmethoxy)-9-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperidine.

Compound 692-([1,4]dioxan-2-ylmethoxy)-9-(2-ethoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and2-ethoxypyridine-3-boronic acid.

Compound 709-(2,6-dimethoxy-pyridin-3-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and2,6-dimethoxy-3-pyridineboronic acid.

Compound 714-[2-([1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-nicotinonitrile

This compound is prepared via general method E using intermediate 11 and3-cyanopyridine-4-boronic acid, pinacol ester.

Compound 729-tert-butoxymethyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 andpotassium tert-butoxymethyltrifluoroborate.

Compound 732-([1,4]dioxan-2-ylmethoxy)-9-(2-pyrrolidin-1-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and2-(pyrrolidin-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

Compound 742-([1,4]dioxan-2-ylmethoxy)-9-(6-pyrrolidin-1-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and2-(1-pyrrolidinyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

Compound 752-([1,4]dioxan-2-ylmethoxy)-9-(5-phenyl-oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 8 and2-chloromethyl-5-phenyl-oxazole.

Compound 769-(5-tert-butyl-oxazol-2-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 8 and5-tert-butyl-2-chloromethyl-oxazole.

Compound 779-(5-cyclopropyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 8 and3-chloromethyl-5-cyclopropyl-[1,2,4]oxadiazole.

Compound 782-([1,4]dioxan-2-ylmethoxy)-9-(5-ethyl-[1,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 8 and3-chloromethyl-5-ethyl-[1,2,4]oxadiazole.

Compound 792-([1,4]dioxan-2-ylmethoxy)-9-(5-methyl-[1,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 8 and3-chloromethyl-5-methyl-[1,2,4]oxadiazole.

Compound 802-([1,4]dioxan-2-ylmethoxy)-9-(5-isopropyl-[1,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 8 and3-chloromethyl-5-isopropyl-[1,2,4]oxadiazole.

Compound 819-cyclopentylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 andethynyl-cyclopentane.

Compound 829-cyclohexylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 andethynyl-cyclohexane.

Compound 832-([1,4]dioxan-2-ylmethoxy)-9-(3-methyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 and3-methyl-but-1-yne.

Compound 842-([1,4]dioxan-2-ylmethoxy)-9-hex-1-ynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 andhex-1-yne.

Compound 859-[3-(benzyl-methyl-amino)-prop-1-ynyl]-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 andbenzyl-methyl-prop-2-ynyl-amine.

Compound 862-([1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-5-methyl-hex-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 and5-methyl-hex-1-yn-3-ol, with iPr₂NH as base and THF as solvent.

Compound 872-([1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 andbut-3-yn-2-ol, with iPr₂NH as base and THF as solvent.

Compound 889-cyclopropyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 andpotassium cyclopropyltrifluoroborate.

Compound 892-([1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 andpent-1-yn-3-ol with iPr₂NH as base and THF as solvent.

Compound 902-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4-methyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 and4-methyl-pent-1-yn-3-ol with iPr₂NH as base and THF as solvent.

Compound 912-([1,4]dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 and3-ethyl-pent-1-yn-3-ol with iPr₂NH as base and THF as solvent.

Compound 922-([1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-3-phenyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 and2-phenyl-but-3-yn-2-ol with Cs₂CO₃ as base and MeCN as solvent underreflux.

Compound 93 9-(3-benzylamino-prop-1-ynyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 andbenzyl-prop-2-ynyl-amine with Cs₂CO₃ as base and MeCN as solvent underreflux.

Compound 942-([1,4]dioxan-2-ylmethoxy)-9-[(furan-2-ylmethyl)-amino]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

A suspension of intermediate 11 (200 mg, 0.433 mmol, 1 eq.),furan-2-ylmethanamine (0.038 mL, 0.433 mmol, 1 eq.) and Cs₂CO₃ (0.17 g,0.519 mmol, 1.2 eq.) in toluene (4 mL) was degassed with Ar for 30 minbefore BINAP (+/−) (16 mg, 0.026 mmol, 0.06 eq.) and Pd(OAc)₂ (3.88 mg,0.017 mmol, 0.04 eq.) were added. The reaction was heated to 65° C. for16 h. The reaction was cooled to RT, BINAP (+/−) (16 mg, 0.026 mmol,0.06 eq.) and Pd(OAc)₂ (3.88 mg, 0.017 mmol, 0.04 eq.) were added andthe reaction was degassed. The reaction was heated to 80° C. for 1 extraday. The reaction was cooled to RT, BINAP (+/−) (16 mg, 0.026 mmol, 0.06eq.) and Pd(OAc)₂ (3.88 mg, 0.017 mmol, 0.04 eq.) were added and thereaction was degassed. The reaction was heated to 80° C. for 1 extraday. The reaction was cooled to RT and diluted with DCM and washed with0.5N aqueous KHSO₄. The aqueous layer was extracted with DCM, thecombined organic layers were dried over Na₂SO₄ and evaporated todryness. The crude product was purified by preparative HPLC-MS [H₂O(98→2): MeCN (2→98)/0.1% HCO₂H] to give compound 94.

(¹H, CDCl₃) δ ppm 7.57-7.48 (1 H , d), 7.38 (1 H , s), 6.68-6.55 (1 H ,d), 6.49 (1 H , s), 6.35 (1 H , s), 6.28 (1 H, s), 6.20 (1 H , s),4.60-4.50 (1 H , m), 4.38-4.30 (4 H , m), 4.22-4.15 (2 H , m), 4.03-3.93(1 H , m), 3.95-3.60 (5 H , m), 3.55-3.40 (1 H , t), 2.98-2.85 (2 H , m)

MW (calcd): 409.4; MW (obsd): 410.2 (M+1)

Compound 952-([1,4]dioxan-2-ylmethoxy)-9-(1-ethyl-1H-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and1-ethyl-1H-pyrazole-4-boronic acid, pinacol ester.

Compound 962-([1,4]dioxan-2-ylmethoxy)-9-[1-(3-methyl-butyl)-1H-pyrazol-4-yl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and1-(3-methylbutyl)-1H-pyrazole-4-boronic acid, pinacol ester.

Compound 972-([1,4]dioxan-2-ylmethoxy)-9-(5-methyl-furan-2-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and2-methylfurane-5-boronic acid pinacol ester.

Compound 982-([1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-hex-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 andhex-1-yn-3-ol, Cs₂CO₃ as base and MeCN as solvent under reflux.

Compound 999-(3,5-dimethyl-1H-pyrazol-4-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and3,5-dimethylpyrazole-4-boronic acid pinacol ester.

Compound 1002-([1,4]dioxan-2-ylmethoxy)-9-(1H-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 andpyrazole-4-boronic acid pinacol ester.

Compound 1012-([1,4]dioxan-2-ylmethoxy)-9-(1-propyl-1H-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 and1-propyl-1H-pyrazole-4-boronic acid, pinacol ester.

Compound 1022-[2-((R)-1-[1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile

This compound is prepared via general method E using intermediate 10 and2-cyanophenylboronic acid pinacol ester.

Compound 1032-[2-((S)-1-[1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile

This compound is prepared via general method E using intermediate 9 and2-cyanophenylboronic acid pinacol ester.

Compound 1049-(5-cyclopropyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 7 and3-chloromethyl-5-cyclopropyl-[1,2,4]oxadiazole.

Compound 1052-([1,4]dioxan-2-ylmethoxy)-9-ethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-([7,4]dioxan-2-ylmethoxy)-9-prop-1-ynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 24)

Intermediate 242-([1,4]dioxan-2-ylmethoxy)-9-prop-1-ynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-oneis synthesised via general method E with intermediate 11 andethynyl-trimethyl-silane.

(¹H, CDCl₃) δ ppm 7.66-7.61 (1 H , m), 7.47-7.43 (1 H , m), 7.42-7.38 (1H , m), 6.37 (1 H , s), 4.50-4.36 (2 H , m), 4.23-4.16 (2 H , m),4.04-3.93 (1 H , m), 3.90-3.60 (4 H , m), 3.53-3.44 (1 H , m), 3.02-2.97(1 H, m), 0.27 (7 H , s)

MW (calcd): 410.5; MW (obsd): 411.4 (M+1)

Step 2:2-([1,4]dioxan-2-ylmethoxy)-9-ethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 105)

TBAF (4.06 mL, 4.06 mmol, 1.2 eq.) was added dropwise to a solution ofintermediate 24 (1.39 g, 3.39 mmol, 1 eq.) in THF (40 mL) at 0° C. andthe reaction was stirred for 1 h at 0° C. The reaction was thenevaporated to dryness, and the residue was re-dissolved in HCl 1N. Theaqueous phase was extracted with DCM, the combined organic layers weredried over MgSO₄ and the solvent evaporated under vacuum. The crudeproduct was purified by flash chromatography on silica gel, eluting from0 to 5% MeOH/DCM to furnish compound 105.

(¹H, CDCl₃) δ ppm 7.65 (1 H , s), 7.51-7.46 (1 H , m), 7.45-7.41 (1 H ,m), 6.37 (1 H , s), 4.49-4.36 (2 H , m), 4.21 (2 H , s), 4.04-3.94 (1 H, m), 3.90-3.61 (5 H , m), 3.53-3.44 (1 H , m), 3.25 (1 H , s), 3.00 (2H , s)

MW (calcd): 330.3; MW (obsd): 331

Compound 1062-([1,4]dioxan-2-ylmethoxy)-9-pyrimidin-2-ylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Compound 105 (50 mg, 0.15 mmol, 1 eq.) was dissolved in DMF (3 mL),5-bromo-pyrimidine (47 mg, 0.30 mmol, 2 eq.) was added followed by TEA(0.062 mL, 0.44 mmol, 3 eq.), and the mixture was degassed. Pd(PPh₃)₃Cl₂(5 mg, 0.0074 mmol, 0.05 eq.) was added with CuI (6 mg, 0.029 mmol, 0.2eq.) and the reaction mixture was heated at 80° C. for 16 h. Thevolatiles were evaporated to dryness and the crude product was purifiedby flash chromatography on silica gel, eluting from 0 to 5% MeOH/DCM togive compound 106.

Compound 1072-([1,4]dioxan-2-ylmethoxy)-9-(3-phenylamino-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 andphenyl-prop-2-ynyl-amine with iPr₂NH as base and THF as solvent.

Compound 1082-([1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 and1-pyridin-3-yl-prop-2-yn-1-ol.

Compound 1099-cyclopentyloxymethyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 11 andpotassium cyclopentoxymethyltrifluoroborate.

Compound 1102-([1,4]dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Synthesis fully described above.

Compound 1119-cyclopropylethynyl-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 10 andethynyl-cyclopropane.

Compound 1122-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-methyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 9 and3-methyl-but-1-yne.

Compound 1132-([1,4]Dioxan-2-ylmethoxy)-9-(3-imidazol-1-yl-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 and1-prop-2-ynyl-1H-imidazole.

Compound 1149-(2-cyclopropyl-ethyl)-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

A round bottom flask was charged with intermediate 10 (2 g, 4.33 mmol, 1eq.), intermediate 20 (1.1 g, 6.5 mmol, 1.5 eq.), K₂CO₃ (1.8 g, 13 mmol,3 eq.), Pd(OAc)₂ (19 mg, 0.087 mmol, 0.02 eq.), RuPhos (81 mg, 0.173mmol, 0.04 eq.), toluene (30 mL) and H₂O (3 mL). The mixture wasdegassed with N₂ and was heated at 80° C. for 16 h. The reaction wascooled to RT, quenched with brine and extracted with EtOAc. The organiclayer was dried over MgSO₄ and evaporated to dryness. The crude productwas purified by flash chromatography on silica gel, eluting from 70 to90% EtOAc/H to give compound 114.

(¹ H , CDCl₃) δ ppm 7.64-7.58 (1 H , m), 7.24-7.19 (1 H , m), 7.13 (1 H, s), 6.35 (1 H , s), 4.49-4.36 (2 H , m), 4.25-4.17 (2 H , m),4.03-3.95 (1 H , m), 3.90-3.61 (5 H , m), 3.54-3.45 (1 H , m), 3.02-2.95(2 H , m), 2.81-2.72 (2 H , m), 1.59-1.49 (2 H , m), 0.77-0.64 (1 H ,m), 0.49-0.42 (2 H , m), 0.10-0.02 (2 H , m)

MW (calcd): 382.5; MW (obsd): 383.4 (M+1)

Compound 1159-cyclopentyloxymethyl-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 10 andpotassium cyclopentoxymethyltrifluoroborate.

Compound 1162-([1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-propyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Synthesis fully described above.

Compound 1179-allyloxy-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Synthesis fully described above.

Compound 1189-allyloxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Synthesis fully described above.

Compound 1192-((R)-1-[1,4]dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-yloxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 10 andintermediate 14.

Compound 1202-([1,4]dioxan-2-ylmethoxy)-9-{3-[(pyridin-3-ylmethyl)-amino]-prop-1-ynyl}-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 11 andprop-2-yn-1-yl(pyridin-3-ylmethyl)amine.

Compound 1212-((R)-1-[1,4]dioxan-2-ylmethoxy)-9-pentyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This Compound is prepared via general method I using compound 111.

Compound 1229-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Intermediate 9 (13.5 g, 29.20 mmol, 1 eq.) was dissolved in degassed DMF(1000 mL) under an nitrogen atmosphere, ethynyl cyclopropane (3.5 g,53.00 mmol, 1.8 eq.) was added followed by Pd(PPh₃)₃Cl₂ (1.11 g, 1.58mmol, 0.05 eq.), CuI (1.9 g, 9.98 mmol, 0.34 eq.) and TEA (12.5 mL, 89.7mmol, 3.1 eq.). The reaction mixture was stirred 3 h at 80° C. and 15 hat room temperature. The reaction was concentrated under vacuum. Thecrude product was then purified by trituration in hot iPrOH to affordcompound 122.

(¹ H , CDCl₃) δ ppm 7.63 (1 H , d), 7.39 (1 H , dd), 7.31 (1 H , s),6.36 (1 H , s), 4.50-4.39 (2 H, m), 4.20 (2 H , t), 4.02-3.98 (1 H , m),3.89-3.66 (5 H , m), 3.49 (1 H , t), 2.96 (2 H , t), 1.59-1.48 (1 H ,m), 0.98-0.81 (4 H , m)

MW (calcd): 378.4; MW (obsd): 379.4

ee=98.3%

Compound 1239-(2-cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one

A round bottom flask was charged with intermediate 9 (2.08 g, 4.51 mmol,1 eq.), intermediate 20 (1.35 g, 7.67 mmol, 1.7 eq.), K₂CO₃ (1.87 g,13.53 mmol, 3 eq.), Pd(OAc)₂ (20 mg, 0.09 mmol, 0.02 eq.), RuPhos (84mg, 0.18 mmol, 0.04 eq.), toluene (30 mL) and H₂O (3 mL). The mixturewas degassed with N₂ and was heated at 80° C. for 1.5 days. The reactionwas cooled to RT and some more reagents were added, potassium2-cyclopropyl-ethyl-trifluoroborate (0.3 eq.), Pd(OAc)₂ (0.02 eq.),RuPhos (0.04 eq.), the reaction was degassed and the reaction was heatedat 80° C. for 16 h. The reaction was cooled to RT, quenched with H₂O andextracted with EtOAc. The organic layer was dried over MgSO₄ andevaporated to dryness. The crude product was purified by flashchromatography on silica gel, eluting from 80 to 90% EtOAc/H to compound123.

(¹H, CDCl₃) δ ppm 7.64-7.58 (1 H , m), 7.24-7.19 (1 H , m), 7.13 (1 H ,s), 6.35 (1 H , s), 4.49-4.36 (2 H , m), 4.24-4.17 (2 H , m), 4.03-3.95(1 H , m), 3.91-3.62 (5 H , m), 3.49 (1 H , dd), 3.03-2.95 (2 H , m),2.81-2.73 (2 H , m), 1.59-1.50 (2 H , m), 0.71 (1 H , s), 0.49-0.42 (2 H, m), 0.09-0.03 (2 H , m)

MW (calcd): 382.5; MW (obsd): 383.4

Compound 1242-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(oxetan-3-yloxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 9 andintermediate 15.

Compound 1252-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-methyl-oxetan-3-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 9 andintermediate 16.

Compound 1269-(2,2-dimethyl-butylamino)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Synthesis fully described above.

Compound 1272-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4-methyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 25)

Intermediate 25 is prepared via general method G using intermediate9,4-Methyl-pent-1-yn-3-ol, iPr₂NH as base and THF as solvent.

(¹H, CDCl₃) δ ppm 7.65-7.60 (1 H , d), 7.48-7.40 (1 H , m), 7.37 (1 H ,s), 6.36 (1 H , s), 4.50-4.30 (3 H , m), 4.25-4.15 (2 H , m), 4.05-3.95(1 H , m), 3.92-3.60 (6 H , m), 3.68-3.40 (1 H , m), 3.05-2.92 (2 H ,m), 2.10-1.95 (1 H , m), 1.93-1.80 (1 H , m), 1.15-1.00 (6 H , m)

MW (calcd): 410.5; MW (obsd): 411.2 (M+1)

Step 2:2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 127)

Compound 127 is prepared via general method I using intermediate 25.

Compound 1282-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(2-ethyl-hexylamino)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method J using intermediate 13 and2-ethyl-hexanal.

Compound 1292-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(2-methoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 6 and1-bromo-2-methoxy-ethane, KI was not used in this experiment.

Compound 1302-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(2-ethoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 6 and1-bromo-2-ethoxy-ethane, KI was not used in this experiment.

Compound 1319-cyclopropylmethoxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 6 andbromomethyl-cyclopropane, KI was not used in this experiment.

Compound 1322-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(2-fluoro-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 6 and1-bromo-2-fluoro-ethane, KI was not used in this experiment.

Compound 1332-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-[3-(2-methoxy-ethoxy)-prop-1-ynyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Synthesis fully described above.

Compound 1342-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-[3-(2-ethoxy-ethoxy)-prop-1-ynyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method K using intermediate 21 and1-bromo-2-ethoxy-ethane.

Compound 1352-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-[3-(2-fluoro-ethoxy)-prop-1-ynyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method K using intermediate 21 and1-bromo-2-fluoro-ethane.

Compound 1369-(2,2-dimethyl-propoxymethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 9, ina mixture of DME/H₂O (2/1), in a microwave at 120° C. for 20 min andintermediate 17.

Compound 1379-cyclohexyloxymethyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 9 andpotassium cyclohexyloxymethyltrifluoroborate in a mixture of DME/H₂O(2/1), in a microwave at 120° C. for 20 min.

Compound 1389-cyclopropylmethoxymethyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 9, ina mixture of DME/H₂O (2/1), in a microwave at 120° C. for 20 min andintermediate 18.

Compound 1392-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method F using intermediate 6 and2-bromomethyl-tetrahydro-pyran, KI was not used in this experiment.

Compound 1402-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 26)

Intermediate 26 was prepared via general method G using intermediate 9and but-3-yn-2-ol, the crude product was used in the next step withoutcharacterization.

Step 2:2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 140)

Compound 140 was prepared via general method I using intermediate 26.

Compound 1419-(4,4-dimethyl-pentyloxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Intermediate 6 (0.1 g, 0.303 mmol, 1 eq.), 4,4-dimethyl-pentan-1-ol (35mg, 0.303 mmol, 1 eq.) and PPh₃ (95 mg, 0.363 mmol, 1.2 eq.) weresuspended in 1,4-dioxane (5 mL) and the mixture was degassed with N₂.DIAD (0.065 mL, 0.333 mmol, 1.1 eq.) was added dropwise and the reactionwas stirred at RT for 2 h. The reaction mixture was evaporated todryness and the residue was purified by preparative TLC eluting withEtOAc to give compound 141.

(¹H, CDCl₃) δ ppm 7.70-7.58 (1 H , d), 6.95-6.82 (1 H , d), 6.77 (1 H ,s), 6.27 (1 H , s), 4.50-4.32 (2 H , m), 4.38-4.15 (2 H , m), 4.05-3.92(3 H , m), 3.92-3.60 (5 H , m), 3.55-3.42 (1 H , t), 3.05-2.92 (2 H ,m), 1.85-1.70 (2 H , m), 1.40-1.30 (2 H , m), 0.92 (9 H , s)

MW (calcd): 428.5; MW (obsd): 429.2 (M+1)

Compound 1422-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 27)

Intermediate 27 is prepared via general method H using intermediate 25.

MW (calcd): 424.5; MW (obsd): 425.2 (M+1)

Step 2:2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 142)

Compound 142 is prepared via general method I using intermediate 27.

Compound 1439-(3-cyclopropyl-propoxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Intermediate 6 (2.12 g, 2.42 mmol, 1 eq.), 4,4-dimethyl-pentan-1-ol(0.77 g, 7.71 mmol, 1.2 eq.) and PPh₃ (2.02 g, 7.71 mmol, 1.2 eq.) weresuspended in 1,4-dioxane (50 mL) and the mixture was degassed with N₂.DIAD (1.56 mL, 7.71 mmol, 1.1 eq.) was added dropwise and the reactionwas stirred at RT for 2 h. The reaction mixture was quenched with brineand extracted with EtOAc, the organic phase was dried over MgSO₄ andevaporated to dryness. Compound 143 was obtained by purification byflash chromatography on silica gel, eluting from 60 to 100% EtOAc/H.

(¹H, CDCl₃) δ ppm 7.66-7.60 (1 H , m), 6.91-6.86 (1 H , m), 6.80-6.76 (1H , m), 6.28 (1 H , s), 4.48-4.35 (2 H , m), 4.24-4.17 (2 H , m),4.11-4.04 (2 H , m), 4.02-3.95 (1 H , m), 3.91-3.61 (5 H , m), 3.54-3.45(1H, m), 3.03-2.94 (2 H , m), 1.98-1.88 (2 H , m), 1.45-1.36 (2 H , m),0.78-0.66 (1 H , m), 0.50-0.43 (2 H , m), 0.09-0.03 (2 H , m)

MW (calcd): 412.5; MW (obsd): 413.5

Compound 1459-cyclohexylamino-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method J using intermediate 13 andcyclohexanone.

Compound 1462-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-4,4-dimethyl-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4,4-dimethyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 28)

Intermediate 28 is prepared via general method G using intermediate 9.

MW (calcd): 424.5; MW (obsd): 425.4 (M+1)

Step 2:2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-4,4-dimethyl-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 146)

Compound 146 is prepared via general method I using intermediate 28.

Compound 1479-cyclopentylmethoxymethyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 9, ina mixture of DME/H₂O (2/1), in a microwave at 120° C. for 20 min andintermediate 19.

Compound 1482-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-methoxy-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 29)

Intermediate 29 is prepared via general method H using intermediate 26.

MW (calcd): 396.4; MW (obsd): 397.2 (M+1)

Step 1:2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-methoxy-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 148)

Compound 148 is prepared via general method I using intermediate 29.

Compound 1492-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-phenylamino-propyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-phenylamino-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 30)

Intermediate 30 is prepared via general method G using intermediate 9and phenyl-prop-2-ynyl-amine.

MW (calcd): 443.5; MW (obsd): 444.2 (M+1)

Step 2:2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-phenylamino-propyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 149)

Compound 149 is prepared via general method I using intermediate 30.

Compound 1502-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(4-hydroxy-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 31)

Intermediate 31 was prepared via general method G using intermediate 9,pent-4-yn-2-ol, iPr₂NH as base and THF as solvent.

MW (calcd): 396.4; MW (obsd): 397.2 (M+1)

Step 2:2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(4-hydroxy-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 150)

Compound 150 was prepared via general method I using intermediate 31.

Compound 1512-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(4-hydroxy-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 32)

Intermediate 32 was prepared via general method G using intermediate 9,but-3-yn-1-ol, iPr₂NH as base and THF as solvent.

(¹H, CDCl₃) δ ppm 7.70-7.65 (1 H , m), 7.45-7.35 (1 H , m), 7.34 (1 H ,s), 6.35 (1 H , s), 4.50-4.32 (2 H , m), 4.28-4.10 (2 H , m), 4.05-3.90(1 H , m), 3.95-3.60 (7 H , m), 3.55-3.40 (1 H , m), 3.05-2.90 (2 H ,m), 2.80-2.65 (2 H , m), 2.00-1.80 (1 H , m)

MW (calcd): 382.4; MW (obsd): 383.2 (M+1)

Step 2:2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(4-hydroxy-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 151)

Compound 151 was prepared via general method I using intermediate 32.

Compound 1529-(cyclohexyl-methyl-amino)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

MeI (0.007 mg, 0.11 mmol, 1.2 eq.) was added to compound 147 (38 mg,0.092 mmol, 1 eq.) and NaH (6 mg, 0.15 mmol, 1.6 eq.) in DMF (5 mL) andthe reaction was stirred at RT for 16 h. Some more NaH (6 mg, 0.15 mmol,1.6 eq.) and MeI (0.07 mg, 0.11 mmol, 1.2 eq.) were added to thereaction mixture and it was stirred for a further 2 days. The mixturewas quenched with brine and extracted with EtOAc. The organic layerswere dried over MgSO₄ and evaporated to dryness. The residue waspurified by preparative HPLC-MS to provide compound 152.

(¹H, CDCl₃) δ ppm 7.57-7.50 (1 H , m), 6.71 (1 H , d), 6.53 (1 H , br.s.), 6.21 (1 H , s), 4.51-4.33 (2 H , m), 4.26-4.14 (2 H , m), 4.06-3.93(1 H , m), 3.92-3.56 (6 H , m), 3.56-3.41 (1 H , m), 3.00-2.90 (2 H ,m), 2.88 (3 H , s), 2.04-1.63 (2 H , m), 1.60-1.31 (5 H , m), 1.28-1.08(1 H , m)

MW (calcd): 425.5; MW (obsd): 426.4

Compound 1539-(cyclohexylmethyl-amino)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method J using intermediate 13 andcyclohexanecarbaldehyde.

Compound 1542-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-[(tetrahydro-pyran-4-ylmethyl)-amino]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method J using intermediate 13 andtetrahydro-pyran-4-carbaldehyde.

Compound 1552-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 33)

Intermediate 33 is prepared via general method G using intermediate 9and 3-ethyl-pent-1-yn-3-ol.

(¹H, CDCl₃) δ ppm 7.51-7.46 (1 H , m), 7.28-7.24 (1 H , m), 7.22-7.19 (1H , m), 6.20 (1 H , s), 4.30-4.19 (2 H , m), 4.08-4.00 (2 H , m),3.87-3.79 (1 H , m), 3.75-3.47 (5 H , m), 3.39-3.30 (1 H , m), 3.03 (1 H, br. S), 2.88-2.80 (2 H , m), 1.746-1.56 (4 H , m), 0.97 (6 H , s)

MW (calcd): 424.5; MW (obsd): 425.5 (M+1)

Step 2:2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 155)

Compound 155 is prepared via general method I using intermediate 33.

Compound 1562-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 34)

Intermediate 34 is prepared via general method G using intermediate 9and 2-methyl-but-3-yn-2-ol.

(¹H, CDCl₃) δ ppm 7.58 (1 H , d), 7.38-7.33 (1 H , m), 7.32-7.29 (1 H ,m), 6.32 (1 H , s), 4.43-4.32 (2 H , m), 4.18-4.12 (2 H , m), 3.99-3.91(1 H , m), 3.87-3.58 (5 H , m), 3.50-3.42 (1 H , m), 2.97-2.90 (2 H ,m), 1.60 (6 H , s)

MW (calcd): 396.4; MW (obsd): 397.3 (M+1)

Step 2:2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 156)

Compound 156 is prepared via general method I using intermediate 34.

Compound 1572-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 35)

Intermediate 35 is prepared via general method G using intermediate 9and pent-1-yn-3-ol.

(¹H, CDCl₃) δ ppm 7.62-7.57 (1 H , m), 7.41-7.35 (1 H , m), 7.33 (1 H ,s), 6.34 (1 H , s), 4.60-4.53 (1 H , m), 4.45-4.33 (2 H , m), 4.20-4.14(2 H , m), 4.00-3.92 (1 H , m), 3.88-3.59 (5 H , m), 3.51-3.42 (1 H ,m), 2.99-2.90 (2 H , m), 1.90-1.74 (2 H , m), 1.07 (3 H , t)

Step 2:2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 157)

Compound 157 is prepared via general method I using intermediate 35.

Compound 1589-(2,2-dimethyl-propoxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Synthesis fully described above.

Compound 1592-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method L with intermediate 6 andmethanesulfonic acid tetrahydro-pyran-4-ylmethyl ester.

Compound 1602-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(4-hydroxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-4-methyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(intermediate 36)

A vial was charged with intermediate 9 (0.15 g, 0.324 mmol, 1 eq.),2-methyl-5-trimethylsilanyl-pent-4-yn-2-ol (66 mg, 0.389 mmol, 1.2 eq),CuI (2.5 mg, 0.013 mmol, 0.04 eq.), iPr₂NH (0.41 mL, 2.92 mmol, 9 eq.)and THF (2 mL). The solution was purged with Ar for 15 min., andPd(PPh₃)Cl₂ (11 mg, 0.016 mmol, 0.05 eq.) was added with TBAF (0.39 mL,0.39 mmol, 1.2 eq., 1M in THF). The vial was sealed and the reaction washeated to 80° C. for 16 h. The reaction mixture was evaporated todryness and the crude product was purified by preparative TLC [DCM/MeOH,98/2] to afford intermediate 362-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(4-hydroxy-4-methyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one.

(¹H, CDCl₃) δ ppm 7.70-7.58 (1 H , m), 7.45-7.38 (1 H , m), 7.35 (1 H ,s), 6.37 (1 H , s), 4.50-4.30 (2 H , m), 4.28-4.15 (2 H , m), 4.05-3.95(1 H , m), 3.95-3.55 (5 H , m), 3.55-3.40 (1 H , m), 3.05-2.95 (2 H ,m), 2.62 (2 H , s), 1.39 (6 H , s)

MW (calcd): 410.5; MW (obsd): 411.4

Step 2:2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(4-hydroxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 160)

Compound 160 is prepared via general method I using intermediate 36.

Compound 1612-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method E using intermediate 9 andpotassium 4-(tetrahydropyranylmethoxy)methyltrifluoroborate.

Compound 1622-([1,4]dioxan-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1: 1-[2-(3-methoxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione(intermediate 37)

Sodium (236 mg, 10.2 mmol, 2 eq.) was added to degassed EtOH (18 mL),when sodium dissolved completely, ethyl malonate (1.56 mL, 10.2 mmol, 2eq.) was added and the reaction was refluxed for 1 h. Intermediate 1(995 mg, 5.12 mmol, 1 eq.) in EtOH (4 mL) was then added and thereaction was refluxed for 1 day. The desired intermediate 371-[2-(3-methoxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione precipitated uponaddition of 2N aqueous HCl, it was filtered and washed with H₂O andfinally dried.

(¹H, DMSO-d₆) δ ppm 7.27-7.18 (1 H , m), 6.84-6.72 (3 H , m), 3.92-3.83(2 H , m), 3.75 (3 H , s), 3.62 (2 H, s), 2.80-2.70 (2 H , m)

MW (calcd): 262.3; MW (obsd): 263.3 (M+1)

Step 2: 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(intermediate 38)

Intermediate 37 (920 mg, 3.51 mmol, 1 eq.) was heated in POCl₃ (5 mL) at50° C. for 2 days. The volatiles were evaporated under vacuum, theresidue was dissolved in DCM and washed with a saturated aqueoussolution of NaHCO₃, before drying over MgSO₄. Evaporation of the organicphase gave intermediate 382-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, whichwas used in the next step without further purification.

(¹H, CDCl₃) δ ppm 7.73-7.66 (1 H , m), 6.98-6.90 (1 H , m), 6.85-6.80 (1H , m), 6.69 (1 H , s), 4.00-4.20 (2 H , m), 3.91 (3 H , s), 3.04 (2 H ,m)

Step 3:2-([1,4]dioxan-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(compound 162)

[1,4]Dioxan-2-yl-methanol (42 mg, 0.36 mmol, 2 eq.) was dissolved in DCM(3 mL) with NaH (14 mg, 0.36 mmol, 2 eq., 60% in mineral oil). After 30min, intermediate 38 (50 mg, 0.18 mmol, 1 eq.) was added to the mixtureand the reaction was stirred at RT for 16 h. The reaction mixture wasevaporated to dryness and the crude product was purified by preparativeHPLC-MS to provide compound 162.

(¹H, CDCl₃) δ ppm 7.68-7.62 (1 H , m), 6.95-6.87 (1 H , m), 6.82-6.77 (1H , m), 6.29 (1 H , s), 4.51-4.35 (2 H , m), 4.26-4.17 (2 H , m),4.05-3.92 (1 H , m), 3.91-3.60 (8 H , m), 3.55-3.44 (1 H , m), 3.04-2.94(2 H, m)

MW (calcd): 344.4; MW (obsd): 345.0

Compound 1632-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(oxetan-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method L using intermediate 6 andmethanesulfonic acid oxetan-3-ylmethyl ester.

Compound 1649-(3-cyclopropyl-propoxy)-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one

A solution of intermediate 6 (1.15 g, 3.48 mmol, 1 eq.) and3-cyclopropan-1-ol (0.349 g, 3.48 mmol, 1 eq.) in 1,4-dioxane wasdegassed with Argon for 10 min. PPh₃ (1.096 g, 4.18 mmol, 1.2 eq.) wasadded and the reaction mixture was degassed with Argon an additional 5min. DIAD (0.745 mL, 3.83 mmol, 1.1 eq.) was added dropwise at 0° C. Thereaction mixture was stirred at RT for 16 h. 3-Cyclopropylpropan-1-ol(0.150 mg, 1.49 mmol, 0.43 eq.) and PPh₃ (0.30 g, 1.14 mmol, 0.33 eq.)were added. The reaction mixture was cooled to 0° C. and DIAD (0.350 mL,1.80 mmol, 5.2 eq.) was added. After 1 h at RT, the reaction mixture wasconcentrated under vacuum and the crude product was purified by flashchromatography on silica-gel to afford compound 164.

(¹H, DMSO-d₆) δ ppm 7.93 (1H, d), 6.97-6.92 (2 H, m), 6.53 (1H, s),4.24-4.23 (2H, m), 4.08 (2H, t), 4.00 (2H, t), 3.98-3.74 (3H, m),3.68-3.57 (2H, m), 3.51-3.48 (1H, m), 3.37 (1H, t), 2.96 (2H, t),1.84-1.80 (2H, m), 1.36-1.30 (2H, m), 0.81-0.63 (1H, m), 0.42-0.39 (2H,m), 0.04-0.02 (2H, m)

MW (calcd): 412.5; MW (obsd): 413.0 (M+1)

Compound 1652-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 39)

Intermediate 39 was prepared via general method G using intermediate 9and 3-methoxy-propyne. (¹H, CDCl₃) δ ppm 7.68 (1 H, d), 7.48 (1 H, d),7.42 (1 H, s), 6.40 (1 H, s), 4.50-4.41 (2 H, m), 4.38 (2 H, s), 4.23 (2H, t), 4.05-3.98 (1 H, m), 3.89-3.70 (5 H, m), 3.55-3.50 (4 H, m), 3.03(2 H, t)

MW (calcd): 382.4; MW (obsd): 383.4 (M+1)

Step 2:2-((S)-1-[7,4]dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 165)

Compound 165 was prepared via general method I using intermediate 39.

Compound 1662-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(1-hydroxy-cyclopentylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 40)

Intermediate 40 is prepared via general method G using intermediate 9and 3-methoxy-propyne.

(¹H, CDCl₃) δ ppm 7.54 (1 H, d), 7.31 (1 H, d), 7.26 (1 H, s), 6.28 (1H, s), 4.39-4.30 (2 H, m), 4.12 (2 H, t), 3.95-3.91 (1 H, m), 3.82-3.58(5 H, m), 3.50 (1 H, m), 3.16 (1 H, s), 2.89 (2 H, t), 2.05-1.98 (4 H,m), 1.90-1.70 (4 H, m)

Step 2:2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 166)

Compound 166 was prepared via general method I using intermediate 40.

Compound 1672-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

This compound is prepared via general method G using intermediate 10 and4-Ethynyl-tetrahydro-pyran-4-ol.

Compound 1682-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 40)

Intermediate 41 is prepared via general method G using intermediate 10and 3-methoxy-propyne. (¹H, CDCl₃) □ ppm 7.56 (1 H, d), 7.48 (1 H, d),7.33 (1 H, s), 6.27 (1 H, s), 4.32-4.27 (2 H, m), 4.23 (2 H, s), 4.08 (2H, t), 3.88-3.85 (1 H, m), 3.76-3.49 (5 H, m), 3.40-3.34 (4 H, m), 2.90(2 H, t)

Step 2:2-((R)-1-[7,4]dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 165)

Compound 168 is prepared via general method I using intermediate 41.

Compound 1692-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Step 1:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(1-hydroxy-cyclopentylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Intermediate 42)

Intermediate 42 is prepared via general method G using intermediate 10and 1-Ethynyl-cyclopentanol.

(¹H, CDCl₃) δ ppm 7.47 (1 H, d), 7.25 (1 H, d), 7.20 (1 H, s), 6.22 (1H, s), 4.32-4.24 (2 H, m), 4.05 (2 H, t), 3.88-3.85 (1H, m), 3.77-3.52(5 H, m), 3.38 (1H, t), 2.83 (2 H, t), 2.02-1.90 (4H, m), 1.85-1.67 (4H,m)

Step 2:2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(1-hydroxy-cyclopentylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one(Compound 169)

Compound 169 is prepared via general method I using intermediate 42.

Compound 1702-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-propoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Intermediate 6 (0.15 g, 0.45 mmol, 1 eq.), 2-Propoxy-ethanol (63 μL,0.55 mmol, 1.2 eq.) and PPh₃ (144 mg, 0.55 mmol, 1.2 eq.) were suspendedin 1,4-dioxane (5 mL) and the mixture was degassed with N₂. DIAD (0.108mL, 0.55 mmol, 1.2 eq.) was added and the reaction was stirred at RTovernight. 0.5 eq. of DIAD and PPh₃ were added, and the reaction mixturewas stirred at room temperature for an extra 2 h. Reaction mixture wasdiluted with brine, extracted with EtOAc, dried over MgSO₄ andconcentrated. Crude product was purified on silicagel column to givecompound 170.

Compound 1712-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-isopropoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Intermediate 6 (0.15 g, 0.45 mmol, 1 eq.), 2-isopropoxy-ethanol (63 μL,0.55 mmol, 1.2 eq.) and PPh₃ (144 mg, 0.55 mmol, 1.2 eq.) were suspendedin 1,4-dioxane (5 mL) and the mixture was degassed with N₂. DIAD (0.108mL, 0.55 mmol, 1.2 eq.) was added and the reaction was stirred at RT for5 h. 0.5 eq. of DIAD and PPh₃ were added, and the reaction mixture wasstirred at room temperature overnight. Reaction mixture was diluted withbrine, extracted with EtOAc, dried over MgSO₄ and concentrated. Thecrude product was purified on silicagel column to give compound 171.

Compound 1722-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-propoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Intermediate 7 (0.25 g, 0.76 mmol, 1 eq.), 2-Propoxy-ethanol (105 μL,0.91 mmol, 1.2 eq.) and PPh₃ (238 mg, 0.91 mmol, 1.2 eq.) were suspendedin 1,4-dioxane (10 mL) and the mixture was degassed with N₂. DIAD (0.180mL, 0.91 mmol, 1.2 eq.) was added and the reaction was stirred at RTovernight. 0.3 eq. of DIAD and PPh₃ were added, and the reaction mixturewas stirred at room temperature for an extra 24 h. Reaction mixture wasdiluted with brine, extracted with EtOAc, dried over MgSO₄ andconcentrated. Crude product was purified on silicagel column to givecompound 172.

Compound 1732-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-isopropoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Intermediate 7 (0.25 g, 0.76 mmol, 1 eq.), 2-isopropoxy-ethanol (105 μL,0.91 mmol, 1.2 eq.) and PPh₃ (238 mg, 0.91 mmol, 1.2 eq.) were suspendedin 1,4-dioxane (10 mL) and the mixture was degassed with N₂. DIAD (0.180mL, 0.91 mmol, 1.2 eq.) was added and the reaction was stirred at RT for5 h. 0.3 eq. of DIAD and PPh₃ were added, and the reaction mixture wasstirred at room temperature overnight. Reaction mixture was diluted withbrine, extracted with EtOAc, dried over MgSO₄ and concentrated. Crudeproduct was purified on silicagel column to give compound 173.

Compound 1742-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-oneStep 1: Potassium 3-methoxy-propyl-trifluoroborate

In a 2-neck round bottom flask equipped with a reflux condenser and anaddition funnel was charged with Mg (471 mg, 19.20 mmol, 3 eq.) and Et₂O(2 mL) under N₂. One drop of neat (2-bromo-ethyl)-cyclopropane was addedfollowed by two drops of dibromoethane. Once the 1^(st) bubblesappeared, 1-Bromo-3-methoxy-propane (1 g, 6.54 mmol, 1 eq.) in Et₂O (10mL) was added dropwise. Upon completion of the addition, the resultingsuspension was stirred at RT for 1 h. In a separate flask, purged withN₂, a solution made of B(OMe)₃ (1.1 mL, 9.81 mmol, 1.5 eq.) in THF (12mL) was cooled to −78° C. To this solution, the 3-methoxy-propylmagnesium bromide suspension was added dropwise via a double endedneedle. The mixture was allowed to stir for 1 h at −78° C. and then waswarmed to RT for 1 h. After cooling the mixture to 0° C., a saturatedaqueous solution of KHF₂ (5.8 mL, 4.5 M, 4.1 eq.) was added dropwise andthe reaction mixture was allowed to warm to RT. After 30 min, thesolution was concentrated in-vacuo. The dried solids were trituratedwith hot acetone and filtered to remove inorganic salts. The resultingfiltrate was concentrated and the solid residue was triturated withEt₂O. Potassium 3-methoxy-propyl-trifluoroborate, intermediate 43, wasfiltered and dried in-vacuo.

(¹H, DMSO-d₆) δ ppm 3.19-3.13 (5 H, m), 1.38-1.29 (2 H, m), −0.1-0.19 (2H, m)

Step 2:2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

Compound 174 is prepared via general method E using intermediates 9 and43.

TABLE II Mass spectral data of the Compounds of the Invention Cpd MW MW# Structures Name (calc) (obsd)  1

9-Allyloxy-2-([1,4]dioxan- 2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 370 371  2

2-([1,4]Dioxan-2- ylmethoxy)-9-pyridin-3-yl- 6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one 391 NA  3

2-([1,4]Dioxan-2- ylmethoxy)-9-pyridin-4-yl- 6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one 391 392  4

2-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]- benzonitrile 415 416  5

3-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]- benzonitrile 415 416  6

4-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]- benzonitrile 415 416  7

[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]- acetonitrile 369 370  8

2-([1,4]Dioxan-2- ylmethoxy)-9-(oxazol-2- ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 411 412  9

2-([1,4]Dioxan-2- ylmethoxy)-9-(pyridin-2- ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 421 422  10

9-(3,5-Dichloro-phenyl)-2- ([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 458 459  11

9-Benzofuran-2-yl-2- ([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 430 NA  12

2-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-indole-1- carboxylic acid tert-butyl ester 529 530 13

2-([1,4]Dioxan-2- ylmethoxy)-9-(1H-indol-2- yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 429 430  14

2-([1,4]Dioxan-2- ylmethoxy)-9-(6-methoxy- pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 421 422  15

2-([1,4]Dioxan-2- ylmethoxy)-9-(6- trifluoromethyl-pyridin-3-yl)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 459 460  16

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-methyl-3H- imidazol-4-ylethynyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 418 419  17

9-(5-tert-Butyl- [1,2,4]oxadiazol-3- ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 468 469  18

5-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine- 2-carboxylic acid methylamide 448 449  19

2-([1,4]Dioxan-2- ylmethoxy)-9-pent-1-ynyl- 6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one 380 381  20

2-([1,4]Dioxan-2- ylmethoxy)-9-(2-pyridin-2- yl-ethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 419 420  21

2-([1,4]Dioxan-2- ylmethoxy)-9-(2-pyrazin-2- yl-ethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 420 421  22

2-([1,4]Dioxan-2- ylmethoxy)-9-(1H-indol-5- yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 429 430  23

2-([1,4]Dioxan-2- ylmethoxy)-9-(2-methoxy- phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 420 421  24

2-([1,4]Dioxan-2- ylmethoxy)-9-(5-methoxy- pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 421 422  25

2-([1,4]Dioxan-2- ylmethoxy)-9-(1H-indazol- 5-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 430 431  26

2-([1,4]Dioxan-2- ylmethoxy)-9-(4-methoxy- phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 420 421  27

3-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]- benzamide 433 434  28

5-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-2-fluoro- benzamide 451 452  29

N-{3-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-phenyl}- acetamide 447 448  30

9-Cyclopropylethynyl-2- ([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 378 379  31

2-([1,4]Dioxan-2- ylmethoxy)-9-(1-hydroxy- cyclopentylethynyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 422 423  32

2-([1,4]Dioxan-2- ylmethoxy)-9-pyrimidin-5- yl-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 392 393  33

9-Cyclohex-1-enyl-2- ([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 394 395  34

2-([1,4]Dioxan-2- ylmethoxy)-9-(1-methyl-1H- indol-5-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 443 444  35

2-([1,4]Dioxan-2- ylmethoxy)-9-(6-methyl- pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 405 406  36

2-([1,4]Dioxan-2- ylmethoxy)-9-pyridin-2- ylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 415 416  37

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-methoxy- prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 382 383  38

5-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pent-4- ynenitrile 391 392  39

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy- prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 368 369  40

2-([1,4]Dioxan-2- ylmethoxy)-9-(4-methoxy- phenylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 444 445  41

2-([1,4]Dioxan-2- ylmethoxy)-9-pyridin-3- ylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 415 416  42

4-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-N- methyl-benzamide 447 NA  43

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-methoxy- phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 420 421  44

9-(2-Chloro-phenyl)-2- ([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 424 425  45

2-([1,4]Dioxan-2- ylmethoxy)-9-(4-hydroxy- but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 382 NA  46

9-(1,5-dimethyl-1H-pyrazol- 3-ylmethoxy)-2- ([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 438 439  47

2-([1,4]Dioxan-2- ylmethoxy)-9-(1-methyl-1H- pyrazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 424 425  48

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-methyl- [1,2,4]oxadiazol-5-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 426 427  49

2-([1,4]Dioxan-2- ylmethoxy)-9-(4-morpholin- 4-yl-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 475 476  50

3-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-4-fluoro- benzamide 451 452  51

3-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-5-fluoro- benzamide 451 452  52

9-(3,3-Dimethyl-but-1- ynyl)-2-([1,4]dioxan-2- ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 394 395  53

2-([1,4]Dioxan-2- ylmethoxy)-9-pyridin-4- ylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 415 416  54

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-methyl- isoxazol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 425 426  55

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy-3- methyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 396 397  56

2-([1,4]Dioxan-2- ylmethoxy)-9-(2-methoxy- pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 421 422  57

2-([1,4]Dioxan-2- ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4-one 314 NA  58

9-(3,6-Dihydro-2H-pyran-4- yl)-2-([1,4]dioxan-2- ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 396 397  59

5-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine- 2-carbonitrile 416 417  60

2-([1,4]Dioxan-2- ylmethoxy)-9-(6- isopropoxyl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 449 450  61

2-([1,4]Dioxan-2- ylmethoxy)-9-(6-ethoxy- pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 435 436  62

2-([1,4]Dioxan-2- ylmethoxy)-9-(6-morpholin- 4-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 476 477  63

9-(2,3-Dimethoxy-phenyl)- 2-([1,4]dioxan-2- ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 450 451  64

9-(3-Chloro-2-methoxy- pyridin-4-yl)-2- ([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 455 456  65

2-([1,4]Dioxan-2- ylmethoxy)-9-(2-methyl- pyridin-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 405 406  66

3-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]- isonicotinonitrile 416 417  67

9-(2,5-Dimethoxy-phenyl)- 2-([1,4]dioxan-2- ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 450 451  68

2-([1,4]Dioxan-2- ylmethoxy)-9-(3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-6,7- dihydro-pyrimido[6,1- a]isoquinolin-4-one474 475  69

2-([1,4]Dioxan-2- ylmethoxy)-9-(2-ethoxy- pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 435 436  70

9-(2,6-Dimethoxy-pyridin- 3-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 451 452  71

4-[2-([1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7- dihydro-4H-pyrimidin[6,1-a]isoquinolin-9-yl]- nicotinonitrile 416 417  72

9-tert-Butoxymethyl-2- ([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 400 401  73

2-([1,4]Dioxan-2- ylmethoxy)-9-(2-pyrrolidin- 1-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 460 461  74

2-([1,4]Dioxan-2- ylmethoxy)-9-(6-pyrrolidin- 1-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 460 461  75

2-([1,4]Dioxan-2- ylmethoxy)-9-(5-phenyl- oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 487 488  76

9-(5-tert-Butyl-oxazol-2- ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 467 NA  77

9-(5-Cyclopropyl- [1,2,4]oxadiazol-3- ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 452 453  78

2-([1,4]Dioxan-2- ylmethoxy)-9-(5-ethyl- [1,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 440 441  79

2-([1,4]Dioxan-2- ylmethoxy)-9-(5-methyl- [1,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 426 427  80

2-([1,4]Dioxan-2- ylmethoxy)-9-(5-isopropyl- [1,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 454 455  81

6-Cyclopentylethynyl-2- ([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 406 407  82

9-Cyclohexylethynyl-2- ([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 420 421  83

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-methyl- but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 380 381  84

2-([1,4]Dioxan-2- ylmethoxy)-9-hex-1-ynyl- 6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one 394 395  85

9-[3-(Benzyl-methyl- amino)-prop-1-ynyl]-2- ([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 471 472  86

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy-5- methyl-hex-1-ynyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 424 425  87

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy- but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 382 383  88

9-Cyclopropyl-2- ([1,4]dioxan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one 354 355  89

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy- pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 396 397  90

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy-4- methyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 410 411  91

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-ethyl-3- hydroxy-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 424 425  92

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy-3- phenyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 458 459  93

9-(3-Benzylamino-prop-1- ynyl)-2-([1,4]dioxan-2- ylmethoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 457 458  94

2-([1,4]Dioxan-2- ylmethoxy)-9-[(furan-2- ylmethyl)-amino]-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 409 410  95

2-([1,4]Dioxan-2- ylmethoxy)-9-(1-ethyl-1H- pyrazol-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 408 409  96

2-([1,4]Dioxan-2- ylmethoxy)-9-[1-(3-methyl-butyl)-1H-pyrazol-4-yl]-6,7- dihydro-pyrimido[6,1- a]isoquinolin-4-one450 451  97

2-([1,4]Dioxan-2- ylmethoxy)-9-(5-methyl- furan-2-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 394 395  98

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy- hex-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 410 411  99

9-(3,5-Dimethyl-1H- pyrazol-4-yl)-2- ([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 408 409 100

2-([1,4]Dioxan-2- ylmethoxy)-9-(1H-pyrazol- 4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 380 381 101

2-([1,4]Dioxan-2- ylmethoxy)-9-(1-propyl-1H- pyrazol-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 422 423 102

2-[2-((R)-1-[1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1- a]isoquinolin-9-yl]- benzonitrile 415 416 103

2-[2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1- a]isoquinolin-9-yl]- benzonitrile 415 416 104

9-(5-Cyclopropyl- [1,2,4]oxadiazol-3- ylmethoxy)-2-((R)-1-[1,4]dioxan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one452 453 105

2-([1,4]Dioxan-2- ylmethoxy)-9-ethynyl-6,7- dihydro-pyrimido[6,1-a]isoquinolin-4-one 338 331 106

2-([1,4]Dioxan-2- ylmethoxy)-9-pyrimidin-2- ylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 416 417 107

2-([1,4]Dioxan-2- ylmethoxy)-9-(3- phenylamino-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 443 444 108

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy-3- pyridin-3-yl-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 445 446 109

9-Cyclopentyloxymethyl-2- ([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 412 413 110

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-methoxy-4- methyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 424 425 111

9-Cyclopropylethynyl-2- ((R)-1-[1,4]dioxan-2- ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 378 379 112

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(3-methyl- but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 380 381 113

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-imidazol-1-yl-prop-1-ynyl)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 418 419114

9-(2-Cyclopropyl-ethyl)-2- ((R)-1-[1,4]dioxan-2- ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 382 383 115

9-Cyclopentyloxymethyl-2- ((R)-1-[1,4]dioxan-2- ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 412 413 116

2-([1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy-3- pyridin-3-yl-propyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 449 450 117

9-Allyloxy-2-((R)-1- [1,4]dioxan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one 370 371 118

9-Allyloxy-2-((S)-1- [1,4]dioxan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one 370 371 119

2-((R)-1-[1,4]Dioxan-2- ylmethoxy)-9-(tetrahydro-pyran-4-yloxymethyl)-6,7- dihydro-pyrimido[6,1- a]isoquinolin-4-one 428429 120

2-([1,4]Dioxan-2- ylmethoxy)-9-{3-[(pyridin- 3-ylmethyl)-amino]-prop-1-ynyl}-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 458 459 121

2-((R)-1-[1,4]Dioxan-2- ylmethoxy)-9-pentyl-6,7- dihydro-pyrimido[6,1-a]isoquinolin-4-one 384 385 122

9-Cyclopropylethynyl-2- ((S)-1-[1,4]dioxan-2- ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 378 379 123

9-(2-Cyclopropyl-ethyl)-2- ((S)-1-[1,4]dioxan-2- ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 382 383 124

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(oxetan-3-yloxymethyl)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 400 401 125

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(3-methyl-oxetan-3-ylmethoxymethyl)- 6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one428 429 126

9-(2,2-Dimethyl- butylamino)-2-((S)-1- [1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 413 414 127

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy-4-methyl-pentyl)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 414 415128

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(2-ethyl- hexylamino)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 441 442 129

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(2-methoxy- ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 388 389 130

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(2-ethoxy- ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 402 403 131

9-Cyclopropylmethoxy-2- ((S)-1-[1,4]dioxan-2- ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 384 385 132

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(2-fluoro- ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 376 377 133

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-[3-(2- methoxy-ethoxy)-prop-1-ynyl]-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 426 427 134

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-[3-(2-ethoxy-ethoxy)-prop-1-ynyl]-6,7- dihydro-pyrimido[6,1- a]isoquinolin-4-one 440441 135

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-[3-(2-fluoro-ethoxy)-prop-1-ynyl]-6,7- dihydro-pyrimido[6,1- a]isoquinolin-4-one 414415 136

9-(2,2-Dimethyl- propoxymethyl)-2-((S)-1- [1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 414 415 137

9-Cyclohexyloxymethyl-2- ((S)-1-[1,4]dioxan-2- ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 426 427 138

9- Cyclopropylmethoxymethyl- 2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 398 399 139

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(tetrahydro-pyran-2-ylmethoxy)-6,7- dihydro-pyrimido[6,1- a]isoquinolin-4-one 428429 140

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy- butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 386 387 141

9-(4,4-Dimethyl-pentyloxy)- 2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 428 429 142

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(3-methoxy-4-methyl-pentyl)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 428 429143

9-(3-Cyclopropyl-propoxy)- 2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 412 413 145

9-Cyclohexylamino-2-((S)- 1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 411 413 146

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy-4,4-dimethyl-pentyl)-6,7- dihydro-pyrimido[6,1- a]isoquinolin-4-one 428429 147

9- Cyclopentylmethoxymethyl- 2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 426 427 148

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(3-methoxy- butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 400 401 149

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(3- phenylamino-propyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 447 448 150

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(4-hydroxy- pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 400 401 151

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(4-hydroxy- butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 386 387 152

9-(Cyclohexyl-methyl- amino)-2-((S)-1- [1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 425 426 153

9-(Cyclohexylmethyl- amino)-2-((S)-1- [1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 425 426 154

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-[(tetrahydro-pyran-4-ylmethyl)-amino]- 6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one427 428 155

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(3-ethyl-3- hydroxy-pentyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 428 429 156

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy-3-methyl-butyl)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 400 401 157

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(3-hydroxy- pentyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 400 401 158

9-(2,2-Dimethyl-propoxy)- 2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 400 401 159

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxy)-6,7- dihydro-pyrimido[6,1- a]isoquinolin-4-one 428429 160

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(4-hydroxy-4-methyl-pentyl)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 414 415161

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxymethyl)- 6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one442 443 162

2-([1,4]Dioxan-2- ylmethoxy)-9-methoxy-6,7- dihydro-pyrimido[6,1-a]isoquinolin-4-one 344 345 163

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(oxetan-3- ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 400 401 164

9-(3-Cyclopropyl-propoxy)- 2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 412 413 165

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(3-methoxy- propyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 386 387 166

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-[2-(1- hydroxy-cyclopentyl)-ethyl]-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 426 427 167

2-((R)-1-[1,4]Dioxan-2- ylmethoxy)-9-(4-hydroxy- tetrahydro-pyran-4-ylethynyl)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 438 168

2-((R)-1-[1,4]Dioxan-2- ylmethoxy)-9-(3-methoxy- propyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 386 387 169

2-((R)-1-[1,4]Dioxan-2- ylmethoxy)-9-[2-(1- hydroxy-cyclopentyl)-ethyl]-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 426 427 170

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(2-propoxy- ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 416 417 171

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(2- isopropoxy-ethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 416 417 172

2-((R)-1-[1,4]Dioxan-2- ylmethoxy)-9-[2-propoxy- ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 416 417 173

2-((R)-1-[1,4]Dioxan-2- ylmethoxy)-9-(2- isopropoxy-ethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 416 417 174

2-((S)-1-[1,4]Dioxan-2- ylmethoxy)-9-(4-methoxy- butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one 400 401 MW: Molecular weight calc:calculated obs: observed

TABLE III NMR Data of the Compounds of the Invention Cpd# NMR data (δ) 1(¹H, CDCl₃) δ□ ppm 7.61 (1 H, d), 6.89 (1 H, dd), 6.78 (1 H, d), 6.26 (1H, s), 6.13-5.94 (1 H, m), 5.48-5.24 (2 H, m), 4.59 (2 H, dt), 4.48-4.30(2 H, m), 4.18 (2 H, t), 4.10-4.02 (1 H, m), 3.96 (1 H, m), 3.89-3.57 (4H, m), 3.46 (1 H, dd), 2.95 (2 H, t) 2 (¹H, CDCl₃) δ ppm 8.89 (1 H, s),8.67 (1 H, d), 7.93 (1 H, d), 7.82 (1 H, d), 7.61 (1 H, d), 7.53 (1 H,s), 7.43 (1 H, dd), 6.43 (1 H, s), 4.51-4.37 (2 H, m), 4.26 (2 H, t),3.99 (1 H, m), 3.92-3.60 (5 H, m), 3.49 (1 H, m), 3.10 (2 H, t) 3 (¹H,CDCl₃) δ ppm 8.77 (2 H, br. s.), 7.86 (1 H, d), 7.76-7.46 (4 H, m), 6.48(1 H, br. s.), 4.60-4.36 (2 H, m), 4.30 (2 H, br. s.), 4.04 (1 H, br.s.), 3.94-3.67 (5 H, m), 3.54 (1 H, t), 3.15 (2 H, br. s.) 4 (¹H, CDCl₃)δ□ ppm 7.83-7.94 (2 H, m), 7.78-7.71 (1 H, m), 7.67-7.53 (4 H, m), 6.48(1 H, s), 4.53-4.43 (2 H, m), 4.34-4.27 (2 H, m), 4.07-4.01 (1 H, m),3.93-3.67 (5 H, m), 3.54 (1 H, dd), 3.14 (2 H, t) 5 (¹H, CDCl₃) δ ppm7.90 (1 H, d), 7.87-7.79(2 H, m), 7.73-7.69 (1 H, m), 7.65- 7.56 (2 H,m), 7.52 (1 H, s), 6.45 (1 H, s), 4.51-4.37 (2 H, m), 4.27 (2 H, t),4.06- 3.95 (1 H, m), 3.91-3.61 (5 H, m), 3.51 (1 H, dd), 3.11 (2 H, t) 6(¹H, CDCl₃) δ ppm 7.85-7.68 (5 H, m), 7.61 (1 H, dd), 7.54 (1 H, d),6.44 (1 H, s), 4.51-4.36 (2 H, m), 4.26 (2 H, t), 4.00 (1 H, m),3.91-3.61 (5 H, m), 3.50 (1 H, dd), 3.11 (2 H, t) 7 (¹H, CDCl₃) δ ppm7.71 (1 H, d), 7.00 (1 H, dd), 6.90 (1 H, d), 6.31 (1 H, s), 4.86 (2 H,s), 4.51-4.34 (2 H, m), 4.22 (2 H, t), 3.99 (1 H, m), 3.92-3.58 (5 H,m), 3.49 (1 H, dd), 3.03 (2 H, t) 8 (¹H, CDCl₃) δ ppm 7.72 (1 H, d),7.68-7.60 (1 H, m), 7.18 (1 H, d), 7.02 (1 H, dd), 6.93 (1 H, d), 6.28(1 H, s), 5.23 (2 H, s), 4.49-4.33 (2 H, m), 4.19 (2 H, t), 4.02-3.94 (1H, m), 3.89-3.61 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, t) 9 (¹H, CDCl₃) δppm 8.63 (1 H, d), 7.75 (1 H, td), 7.64 (1 H, d), 7.50 (1 H, d), 7.29-7.24 (1 H, m), 6.99 (1 H, dd), 6.89 (1 H, d), 6.27 (1 H, s), 5.29 (2 H,d), 4.48- 4.34 (2 H, m), 4.19 (2 H, t), 4.02-3.93 (1 H, m), 3.90-3.60 (5H, m), 3.48 (1 H, dd), 2.97 (2 H, t) 10 (¹H, CDCl₃) δ ppm 7.79 (1 H, d),7.56 (1 H, d), 7.49 (3 H, d), 7.40 (1 H, s), 6.42 (1 H, s), 4.51-4.36 (2H, m), 4.25 (2 H, t), 4.00 (1 H, m), 3.91-3.60 (5 H, m), 3.50 (1 H, t),3.09 (2 H, t) 11 (¹H, CDCl₃) δ ppm 7.87 (1 H, d), 7.83-7.76 (2 H, m),7.64 (1 H, d), 7.56 (1 H, d), 7.41-7.32 (1 H, m), 7.31-7.23 (3 H, m),7.18 (1 H, s), 6.43 (1 H, s), 4.46 (2 H, br. s.), 4.27 (2 H, t),4.06-3.96 (1 H, m), 3.97-3.61 (5 H, m), 3.51 (1 H, t), 3.11 (2 H, t) 12(¹H, CDCl₃) δ ppm 8.20 (1 H, d), 7.76 (1 H, d), 7.60 (1 H, d), 7.47 (1H, dd), 7.42- 7.35 (2 H, m), 7.336-7.26 (1 H, m), 6.68 (1 H, s), 6.44 (1H, s), 4.54-4.40 (2 H, m), 4.27 (2 H, t), 4.08-3.96 (1 H, m), 3.91-3.65(5 H, m), 3.52 (1 H, dd), 3.08 (2 H, t), 1.42 (9 H, s) 13 (¹H DMSO-d₆) δppm 8.11 (1 H, d), 7.95-7.86 (2 H, m), 7.57 (1 H, d), 7.43 (1 H, d),7.15 (1 H, t), 7.10 (1 H, d), 6.71 (1 H, s), 4.31-4.25 (2 H, m), 4.09 (2H, t), 3.92-3.84 (1 H, m), 3.79 (2 H, td), 3.71-3.57 (2 H, m), 3.55-3.46(1 H, m), 3.40 (1 H, dd), 3.08 (2 H, t) 14 (¹H, CDCl₃) δ □ppm 8.45 (1 H,d), 7.84 (1 H, dd), 7.79 (1 H, d), 7.56 (1 H, dd), 7.50-7.46 (1 H, m),6.87 (1 H, d), 6.43 (1 H, s), 4.49-4.36 (2 H, m), 4.30-4.19 (2 H, m),4.04-3.98 (4 H, m), 3.93-3.62 (5 H, m), 3.51 (1 H, dd), 3.10 (2 H, t) 15(¹H, CDCl₃) δ ppm 8.97 (1 H, d), 8.09 (1 H, dd), 7.83 (2 H, dd), 7.63 (1H, dd), 7.55 (1 H, s), 6.44 (1 H, s), 4.52-4.36 (2 H, m), 4.27 (2 H, t),3.99 (1 H, tt), 3.91- 3.59 (5 H, m), 3.49 (1 H, dd), 3.13 (2 H, t) 16(¹H, CDCl₃) δ ppm 7.73 (1 H, d), 7.57-7.50 (2 H, m), 7.48-7.45 (1 H, m),7.42 (1 H, d), 6.42 (1 H, s), 4.53-4.39 (2 H, m), 4.28-4.23 (2 H, m),4.07-3.97 (1 H, m), 3.94-3.64 (8 H, m), 3.52 (1 H, dd), 3.06 (2 H, t) 17(¹H, CDCl₃) δ ppm 7.66 (1 H, d), 7.03 (1 H, dd), 6.94 (1 H, d), 6.29 (1H, s), 5.22 (2 H, s), 4.50-4.33 (2 H, m), 4.27-4.14 (2 H, m), 4.03-3.93(1 H, m), 3.90- 3.61 (5 H, m), 3.49 (1 H, dd), 2.99 (2 H, t), 1.47 (9 H,s) 18 (¹H, CDCl₃) δ ppm 8.80 (1 H, d), 8.32 (1 H, d), 8.16-7.96 (2 H,m), 7.85 (1 H, d), 7.65 (1 H, dd), 7.57 (1 H, s), 6.45 (1 H, s),4.56-4.37 (2 H, m), 4.28 (2 H, t), 4.01 (1 H, qd), 3.93-3.60 (5 H, m),3.58-3.44 (1 H, m), 3.20-3.02 (5 H, m) 19 (¹H, CDCl₃) δ ppm 7.65 (1 H,d), 7.41 (1 H, dd), 7.36 (1 H, s), 6.38 (1 H, s), 4.50- 4.40 (2 H, m),4.28-4.18 (2 H, m), 4.01 (1 H, m), 3.92-3.66 (5 H, m), 3.52 (1 H, dd),3.01 (2 H, t), 2.45 (2 H, t), 1.68 (2 H, sxt), 1.09 (3 H, t) 20 (¹H,CDCl₃) δ ppm 8.58 (1 H, dd), 7.66-7.56 (2 H, m), 7.22 (1 H, dd),7.19-7.09 (3 H, m), 6.36 (1 H, s), 4.50-4.36 (2 H, m), 4.25-4.17 (2 H,m), 4.04-3.95 (1 H, m), 3.91-3.62 (5 H, m), 3.50 (1 H, dd), 3.14 (4 H,s), 2.98 (2 H, t) 21 (¹H, CDCl₃) δ ppm 8.55 (1 H, dd), 8.44 (2 H, dd),7.63 (1 H, d), 7.22 (1 H, dd), 7.15 (1 H, s), 6.36 (1 H, s), 4.53-4.36(2 H, m), 4.26-4.17 (2 H, m), 4.07-3.95 (1 H, m), 3.93-3.61 (5 H, m),3.51 (1 H, dd), 3.17 (4 H, s), 2.99 (2 H, t) 22 (¹H, CDCl₃) δ ppm 8.51(1 H, br. s.), 7.94 (1 H, s), 7.79-7.67 (2 H, m), 7.61 (1 H, s),7.58-7.47 (2 H, m), 7.33 (1 H, t), 6.67 (1 H, br. s.), 6.43 (1 H, s),4.56-4.40 (2 H, m), 4.29 (2 H, t), 4.04 (1 H, td), 3.97-3.65 (5 H, m),3.61-3.48 (1 H, m), 3.11 (2 H, t) 23 (¹H, CDCl₃) δ ppm 7.76 (1 H, d),7.58 (1 H, d), 7.50 (1 H, s), 7.45-7.32 (2 H, m), 7.13-7.01 (2 H, m),6.43 (1 H, s), 4.45 (2 H, m), 4.27 (2 H, t), 4.01 (1 H, m), 3.94- 3.63(8 H, m), 3.52 (1 H, t), 3.08 (2 H, t) 24 (¹H, CDCl₃) δ□ ppm 8.56-8.45(1 H, m), 8.38 (1 H, d), 7.83 (1 H, d), 7.63 (1 H, dd), 7.54 (1 H, s),7.42 (1 H, t), 6.45 (1 H, s), 4.54-4.36 (2 H, m), 4.31-4.23 (2 H, m),4.05-3.96 (4 H, m), 3.93-3.62 (5 H, m), 3.52 (1 H, dd), 3.13 (2 H, t) 25(¹H, CDCl₃) δ ppm 8.17 (1 H, d), 8.01 (1 H, s), 7.78 (1 H, d), 7.72-7.60(3 H, m), 7.57 (1 H, d), 6.42 (1 H, s), 4.52-4.38 (2 H, m), 4.32-4.24 (2H, m), 4.01 (1 H, qd), 3.93-3.62 (5 H, m), 3.51 (1 H, dd), 3.10 (2 H, t)26 (¹H, CDCl₃) δ ppm 7.74 (1 H, d), 7.57 (3 H, d), 7.48 (1 H, s), 7.01(2 H, d), 6.40 (1 H, s), 4.51-4.36 (2 H, m), 4.25 (2 H, t), 3.99 (1 H,dd), 3.92-3.60 (8 H, m), 3.50 (1 H, t), 3.06 (2 H, t) 27 (¹H, CDCl₃) δ□ppm 8.18 (1 H, s), 7.84 (3 H, d), 7.68 (1 H, dd), 7.64-7.55 (2 H, m),6.47 (1 H, s), 4.57-4.39 (2 H, m), 4.30 (2 H, t), 4.09-3.98 (1 H, m),3.96- 3.64 (5 H, m), 3.54 (1 H, dd), 3.13 (2 H, t) 28 (¹H, CDCl₃) δ ppm8.45 (1 H, dd), 7.88-7.74 (2 H, m), 7.65 (1 H, d), 7.58 (1 H, s),7.36-7.25 (1 H, m), 6.46 (1 H, s), 4.57-4.40 (2 H, m), 4.29 (2 H, t),4.03 (1 H, td), 3.96-3.64 (5 H, m), 3.60-3.46 (1 H, m), 3.12 (2 H, t) 29(¹H, CDCl₃) δ□ppm 7.99 (1 H, s), 7.80 (1 H, d), 7.64 (1 H, d), 7.56 (1H, s), 7.50- 7.32 (3 H, m), 6.45 (1 H, s), 4.56-4.40 (2 H, m), 4.29 (2H, t), 4.11-3.97 (1 H, m), 3.95-3.64 (5 H, m), 3.60-3.46 (1 H, m), 3.11(2 H, t), 2.26 (5 H, s) 30 (¹H, CDCl₃) δ ppm 7.63 (1 H, d), 7.39 (1 H,dd), 7.33 (1 H, s), 6.41-6.34 (1 H, m), 4.53-4.39 (2 H, m), 4.29-4.18 (1H, m), 4.06-3.97 (1 H, m), 3.93-3.64 (5 H, m), 3.52 (1 H, dd), 3.00 (2H, t), 1.56-1.45 (1 H, m), 1.01-0.83 (4 H, m) 31 (¹H, CDCl₃) δ ppm 7.67(1 H, d), 7.45 (1 H, dd), 7.39 (1 H, s), 6.40 (1 H, s), 4.53- 4.38 (2 H,m), 4.31-4.17(2 H, m), 4.02 (1 H, dd), 3.94-3.64 (5 H, m), 3.52 (1 H,dd), 3.08-2.96 (2 H, m), 2.18-1.75 (7 H, m), 1.29 (1 H, s) 32 (¹H,CDCl₃) δ□ ppm 9.32 (1 H, s), 9.04 (2 H, s), 7.90 (1 H, d), 7.66 (1 H,dd), 7.58 (1 H, s), 6.48 (1 H, s), 4.56-4.40 (2 H, m), 4.37-4.27 (2 H,m), 4.11-3.99 (1 H, m), 3.96-3.64 (5 H, m), 3.60-3.46 (1 H, m), 3.17 (2H, t) 33 (¹H, CDCl₃) δ ppm 7.67 (1 H, d), 7.42 (1 H, d), 7.32 (1 H, s),6.39 (1 H, s), 6.31 (1 H, t), 4.54-4.38 (2 H, m), 4.25 (2 H, t), 4.02 (1H, dd), 3.94-3.64 (5 H, m), 3.53 (1 H, t), 3.03 (2 H, t), 2.45 (2 H, d),2.29 (2 H, dd), 1.91-1.58 (4 H, m) 34 (¹H, DMSO-d₆) δ ppm 8.07 (1 H, d),7.97 (1 H, s), 7.78-7.72 (2 H, m), 7.62- 7.53 (2 H, m), 7.39 (1 H, d),6.68 (1 H, s), 6.52 (1 H, d), 4.33-4.24 (2 H, m), 4.09 (2 H, t),3.91-3.76 (5 H, m), 3.71-3.58 (2 H, m), 3.55-3.47 (1 H, m), 3.40 (1 H,m), 3.29 (1 H, s), 3.10 (2 H, t) 35 (¹H, CDCl₃) δ □ppm 8.84 (1 H, d),7.96 (1 H, d), 7.85 (1 H, d), 7.64 (1 H, dd), 7.56 (1 H, s), 7.40 (1 H,d), 6.47 (1 H, s), 4.55-4.40 (2 H, m), 4.37-4.23 (2 H, m), 4.04 (1 H,m), 3.95-3.65 (5 H, m), 3.54 (1 H, dd), 3.14 (2 H, t), 2.74 (3 H, s) 36(¹H, CDCl₃) δ□ ppm 8.69 (1 H, d), 7.78-7.72 (2 H, m), 7.65-7.57 (3 H,m), 7.33 (1 H, m), 6.43 (1 H, s), 4.54-4.39 (2 H, m), 4.27 (2 H, t),4.05 (1 H, s), 3.95- 3.64 (5 H, m), 3.53 (1 H, dd), 3.07 (2 H, t) 37(¹H, CDCl₃) δ□ ppm 7.68 (1 H, d), 7.47 (1 H, dd), 7.42 (1 H, s), 6.40 (1H, s), 4.53-4.41 (2 H, m), 4.38 (2 H, s), 4.24 (2 H, t), 4.07-3.96 (1 H,m), 3.93-3.63 (5 H, m), 3.55-3.33 (4 H, m), 3.03 (2 H, t) 38 (¹H, CDCl₃)δ□ ppm 7.67 (1 H, d), 7.44 (1 H, dd), 7.39 (1 H, s), 6.39 (1 H, s),4.50-4.40 (2 H, m), 4.26-4.20 (2 H, m), 4.04-3.98 (1 H, m), 3.91-3.65 (5H, m), 3.52 (1 H, dd), 3.02 (2 H, t), 2.90-2.83 (2 H, m), 2.75-2.68 (2H, m) 39 (¹H, CDCl₃) δ □ppm 7.64 (1 H, d), 7.42 (1 H, dd), 7.37 (1 H,s), 6.38 (1 H, s), 4.51 (2 H, s), 4.48-4.378 (2 H, m), 4.19 (2 H, t),4.03-3.96 (1 H, m), 3.89-3.64 (5 H, m), 3.51 (1 H, dd), 2.99 (2 H, t) 40(¹H, CDCl₃) δ □ppm 7.65 (1 H, d), 7.50-7.44 (3 H, m), 7.41 (1 H, s),6.94-6.84 (2 H, m), 6.35 (1 H, s), 4.45-4.36 (2 H, m), 4.19 (2 H, t),4.04-3.91 (1 H, m), 3.87-3.62 (8 H, m), 3.48 (1 H, dd), 7.81 (1 H, d),7.59-7.48 (2 H, m), 7.43 (1 H, s), 7.41-7.33 (3 H, m), 6.47 (1 H, s),4.54-4.42 (2 H, m), 4.30 (2 H, t), 4.03 (1 H, dt), 3.95-3.65 (5 H, m),3.54 (1 H, dd), 3.11 (2 H, t) 41 (¹H, CDCl₃) δ ppm 8.78 (1 H, d), 8.59(1 H, dd), 7.83 (1 H, dt), 7.71 (1 H, d), 7.54 (1 H, dd), 7.49 (1 H, s),7.39-7.25 (1 H, m), 6.40 (1 H, s), 4.51-4.33 (2 H, m), 4.30-4.16 (2 H,m), 4.07-3.93 (1 H, m), 3.90-3.59 (5 H, m), 3.49 (1 H, dd), 3.04 (2 H,t) 42 (¹H, CDCl₃) δ ppm 7.93 (2 H, d), 7.78 (1 H, d), 7.72-7.59 (3 H,m), 7.54 (1 H, s), 6.42 (1 H, s), 4.49-4.35(2 H, m), 4.23 (2 H, t),4.05-3.95 (1 H, m), 3.91-3.61 (5 H, m), 3.49 (1 H, t), 3.16-2.97 (5 H,m) 43 (¹H, CDCl₃) δ ppm 7.81 (1 H, d), 7.64 (1 H, d), 7.55 (1 H, br.s.), 7.50-7.37 (1 H, m), 7.24 (1 H, d), 7.18 (1 H, br. s.), 7.00 (1 H,d), 6.46 (1 H, br. s.), 4.47 (2 H, d), 4.30 (2 H, br. s.), 4.04 (1 H,br. s.), 3.98-3.66 (7 H, m), 3.54 (1 H, t), 3.12 (2 H, br. s.), 1.83 (1H, br. s.) 44 (¹H, CDCl₃) δ ppm 7.81 (1 H, d), 7.59-7.48 (2 H, m), 7.43(1 H, s), 7.41-7.33 (3 H, m), 6.47 (1 H, s), 4.54-4.42 (2 H, m), 4.30 (2H, t), 4.03 (1 H, dt), 3.95-3.65 (5 H, m), 3.54 (1 H, dd), 3.11 (2 H, t)45 (¹H, CDCl₃) δ ppm 7.62 (1 H, d), 7.39 (1 H, d), 7.34 (1 H, s), 6.36(1 H, s), 4.51- 4.34 (2 H, m), 4.19 (2 H, t), 3.99 (1 H, td), 3.91-3.59(7 H, m), 3.50 (1 H, dd), 2.98 (2 H, t), 2.74 (2 H, t) 46 (¹H, CDCl₃) δppm 7.64 (1 H, d), 7.02 (1 H, dd), 6.92 (1 H, d), 6.30 (1 H, s), 6.13 (1H, s), 5.09 (2 H, s), 4.51-4.36 (2 H, m), 4.22 (2 H, t), 4.07-3.97 (1 H,m), 3.92-3.61 (8 H, m), 3.57-3.44 (1 H, m), 2.99 (2 H, t), 2.30 (3 H, s)47 (¹H, CDCl₃) δ□ppm 7.62 (1 H, d), 7.37 (1 H, d), 7.00 (1 H, dd), 6.90(1 H, d), 6.33 (1 H, d), 6.27 (1 H, s), 5.12 (2 H, s), 4.47-4.34 (2 H,m), 4.23-4.143 (2 H, m), 4.02-3.89 (4 H, m), 3.88-3.59 (5 H, m), 3.48 (1H, dd), 2.96 (2 H, t) 48 (¹H, CDCl₃) δ ppm 7.67 (1 H, d), 6.99 (1 H,dd), 6.90 (1 H, d), 6.29 (1 H, s), 5.33 (2 H, s), 4.47-4.35 (2 H, m),4.20 (2 H, t), 4.03-3.93 (1 H, m), 3.89-3.60 (5 H, m), 3.48 (1 H, dd),2.99 (2 H, t), 2.45 (3 H, s) 49 (¹H, CDCl₃) δ ppm 7.77 (1 H, d),7.66-7.57 (3 H, m), 7.52 (1 H, d), 7.04 (2 H, d), 6.43 (1 H, s),4.55-4.40 (2 H, m), 4.35-4.24 (2 H, m), 4.04 (1 H, dd), 3.97-3.66 (9 H,m), 3.54 (1 H, dd), 3.32-3.20 (4 H, m), 3.10 (2 H, s) 50 (¹H, CDCl₃) δppm 8.06 (1 H, dd), 7.92-7.78 (2 H, m), 7.63 (1 H, d), 7.56 (1 H, s),7.36-7.24 (1 H, m), 6.47 (1 H, s), 4.55-4.38 (2 H, m), 4.28 (2 H, t),4.13- 3.99 (1 H, m), 3.95-3.65 (5 H, m), 3.54 (1 H, t), 3.11 (2 H, t) 51(¹H, CDCl₃) δ ppm 7.95 (1 H, t), 7.80 (1 H, d), 7.67-7.54 (3 H, m),7.54-7.45 (1 H, m), 6.44 (1 H, s), 4.52-4.35 (2 H, m), 4.31-4.19 (2 H,m), 4.09-3.96 (1 H, m), 3.95-3.64 (5 H, m), 3.58-3.46 (1 H, m), 3.10 (2H, t) 52 (¹H, CDCl₃) δ ppm 7.64 (1 H, d), 7.40 (1 H, dd), 7.35 (1 H, d),6.38 (1 H, s), 4.52- 4.39 (2 H, m), 4.26-4.16 (2 H, m), 4.04-3.96 (1 H,m), 3.93-3.63 (5 H, m), 3.51 (1 H, dd), 3.00 (2 H, t), 1.36 (9 H, s) 53(¹H, CDCl₃) δ ppm 8.72-8.64 (2 H, m), 7.75 (1 H, d), 7.59 (1 H, dd),7.54 (1 H, s), 7.48-7.42 (2 H, m), 6.44 (1 H, s), 4.55-4.39 (2 H, m),4.34-4.22 (2 H, m), 4.03 (1 H, dd), 3.95-3.64 (5 H, m), 3.53 (1 H, dd),3.08 (2 H, t) 54 (¹H, CDCl₃) δ ppm 7.68 (1 H, d), 6.98 (1 H, dd), 6.89(1 H, d), 6.31 (1 H, s), 6.23 (1 H, s), 5.22 (2 H, s), 4.52-4.36 (2 H,m), 4.29-4.18 (2 H, m), 4.07-3.96 (1 H, m), 3.93-3.63 (5 H, m), 3.51 (1H, dd), 3.06-2.96 (2 H, m), 2.35 (3 H, s) 55 (¹H, CDCl₃) δ ppm 7.60 (1H, d), 7.39-7.35 (1 H, m), 7.32 (1 H, d), 6.33 (1 H, s), 4.45-4.35 (2 H,m), 4.17 (2 H, t), 3.97 (1 H, m), 3.87-3.60 (5 H, m), 3.47 (1 H, dd),2.95 (2 H, t), 1.62 (6 H, s) 56 (¹H, CDCl₃) δ ppm 8.24 (1 H, dd), 7.78(1 H, d), 7.67 (1 H, dd), 7.61 (1 H, dd), 7.54 (1 H, s), 7.04 (1 H, dd),6.45 (1 H, s), 4.52-4.41 (2 H, m), 4.28 (2 H, t), 4.02 (4 H, s),3.93-3.64 (5 H, m), 3.52 (1 H, dd), 3.10 (2 H, t) 58 (¹H, CDCl₃) δ ppm7.70 (1 H, d), 7.43 (1 H, dd), 7.33 (1 H, d), 6.39 (1 H, s), 6.31 (1 H,dt), 4.53-4.34 (4 H, m), 4.31-4.19 (2 H, m), 4.06-3.94 (3 H, m), 3.92-3.61 (5 H, m), 3.51 (1 H, dd), 3.04 (2 H, t), 2.62-2.50 (2 H, m) 59 (¹H,CDCl₃) δ ppm 9.02 (1 H, d), 8.09 (1 H, dd), 7.97-7.80 (2 H, m), 7.67 (1H, dd), 7.59 (1 H, d), 6.48 (1 H, s), 4.56-4.38 (2 H, m), 4.36-4.25 (2H, m), 4.03 (1 H, m), 3.95-3.63 (5 H, m), 3.53 (1 H, dd), 3.16 (2 H, t)60 (¹H, CDCl₃) δ ppm 8.43 (1 H, d), 7.86-7.74 (2 H, m), 7.56 (1 H, dd),7.47 (1 H, d), 6.80 (1 H, d), 6.43 (1 H, s), 5.44-5.31 (1 H, m),4.53-4.37 (2 H, m), 4.26 (2 H, t), 4.01 (1 H, m), 3.92-3.62 (5 H, m),3.51 (1 H, dd), 3.09 (2 H, t), 1.40 (6 H, d) 61 (¹H, CDCl₃) δ ppm 8.44(1 H, d), 7.84 (1 H, dd), 7.79 (1 H, d), 7.57 (1 H, dd), 7.48 (1 H, d),6.85 (1 H, d), 6.43 (1 H, s), 4.54-4.37 (4 H, m), 4.27 (2 H, t), 4.02 (1H, m), 3.93-3.62 (5 H, m), 3.52 (1 H, dd), 3.10 (2 H, t), 1.45 (3 H, t)62 (¹H, CDCl₃) δ ppm 8.52 (1 H, d), 7.85-7.72 (2 H, m), 7.56 (1 H, dd),7.47 (1 H, d), 6.75 (1 H, d), 6.42 (1 H, s), 4.52-4.38 (2 H, m),4.32-4.22 (2 H, m), 4.06- 3.97 (1 H, m), 3.93-3.58 (13 H, m), 3.52 (1 H,dd), 3.09 (2 H, s) 63 (¹H, CDCl₃) δ ppm 7.77 (1 H, d), 7.60 (1 H, dd),7.52 (1 H, d), 7.21-7.12 (1 H, m), 6.99 (2 H, ddd), 6.45 (1 H, s),4.53-4.40 (2 H, m), 4.28 (2 H, t), 4.06-3.98 (1 H, m), 3.95 (3 H, s),3.92-3.63 (8 H, m), 3.52 (1 H, dd), 3.08 (2 H, t) 64 (¹H, CDCl₃) δ ppm8.15 (1 H, d), 7.82 (1 H, d), 7.50 (1 H, dd), 7.45-7.40 (1 H, m), 6.91(1 H, d), 6.46 (1 H, s), 4.54-4.40 (2 H, m), 4.29 (2 H, t), 4.11 (2 H,s), 4.07-3.98 (1 H, m), 3.94-3.64 (4 H, m), 3.53 (1 H, dd), 3.11 (2 H,t) 65 (¹H, CDCl₃) δ ppm 8.62 (1 H, d), 7.84 (1 H, d), 7.67 (1 H, dd),7.59 (1 H, d), 7.42 (1 H, s), 7.36 (1 H, dd), 6.46 (1 H, s), 4.54-4.38(2 H, m), 4.33-4.24 (2 H, m), 4.07-3.97 (1 H, m), 3.94-3.63 (5 H, m),3.52 (1 H, dd), 3.13 (2 H, t), 2.68 (3 H, s) 66 (¹H, CDCl₃) δ ppm 8.88(1 H, s), 8.82 (1 H, d), 7.88 (1 H, d), 7.68 (1 H, dd), 7.61 (1 H, dd),7.53 (1 H, s), 6.45 (1 H, s), 4.49-4.38 (2 H, m), 4.27 (2 H, t), 4.00 (1H, ddt), 3.90-3.61 (5 H, m), 3.49 (1 H, dd), 3.13 (2 H, t) 67 (¹H,CDCl₃) δ ppm 7.76 (1 H, d), 7.58 (1 H, dd), 7.50 (1 H, s), 6.88-7.03 (3H, m), 6.44 (1 H, s), 4.54-4.39 (2 H, m), 4.28 (2 H, t), 4.03 (1 H, m),3.95-3.63 (11 H, m), 3.53 (1 H, dd), 3.08 (2 H, t) 68 (¹H, CDCl₃) δ ppm8.50 (1 H, d), 7.74 (2 H, td), 7.55 (1 H, dd), 7.45 (1 H, s), 6.75 (1 H,d), 6.40 (1 H, s), 4.56-4.38 (2 H, m), 4.26 (2 H, t), 4.01 (1 H, m),3.94- 3.58 (9 H, m), 3.52 (1 H, dd), 3.08 (2 H, t), 1.70 (6 H, br. s.)69 (¹H, CDCl₃) δ ppm 8.21 (1 H, dd), 7.78 (1 H, d), 7.66 (2 H, ddd),7.56 (1 H, s), 7.01 (1 H, dd), 6.45 (1 H, s), 4.54-4.39 (4 H, m), 4.28(2 H, t), 4.03 (1 H, m), 3.94-3.64 (5 H, m), 3.53 (1 H, dd), 3.09 (2 H,t), 1.42 (3 H, t) 70 (¹H, CDCl₃) δ ppm 7.75 (1 H, d), 7.64 (1 H, d),7.60 (1 H, dd), 7.52 (1 H, d), 6.47 (1 H, d), 6.43 (1 H, s), 4.53-4.39(2 H, m), 4.33-4.23 (2 H, m), 4.03 (6 H, d), 3.94-3.64 (5 H, m),3.59-3.48 (2 H, m), 3.08 (2 H, t) 71 (¹H, CDCl₃) δ ppm 9.00 (1 H, s),8.87 (1 H, d), 7.87 (1 H, d), 7.63 (1 H, dd), 7.56 (1 H, s), 7.52-7.48(1 H, m), 6.45 (1 H, s), 4.51-4.36 (2 H, m), 4.26 (2 H, t), 3.99 (1 H,ddt), 3.90-3.60 (5 H, m), 3.54-3.44 (1 H, m), 3.12 (2 H, t) 72 (¹H,CDCl₃) δ ppm 7.65 (1 H, d), 7.34 (1 H, d), 7.30 (1 H, s), 6.36 (1 H, s),4.48 (2 H, s), 4.46-4.34 (2 H, m), 4.18 (2 H, t), 4.02-3.92 (1 H, m),3.89-3.60 (5 H, m), 3.54-3.42 (1 H, m), 3.00 (2 H, t), 1.30 (9 H, s) 73(¹H, CDCl₃) δ ppm 8.19 (1 H, dd), 7.69 (1 H, d), 7.38 (2 H, ddd), 7.29(1 H, d), 6.72 (1 H, dd), 6.40 (1 H, s), 4.47-4.37 (2 H, m), 4.24 (2 H,t), 4.03-3.93 (1 H, m), 3.89-3.59 (5 H, m), 3.49 (1 H, t), 3.18-3.08 (4H, m), 3.04 (2 H, t), 1.82-1.72 (4 H, m) 74 (¹H, CDCl₃) δ ppm 8.51 (1 H,d), 7.75 (2 H, td), 7.56 (1 H, dd), 7.46 (1 H, s), 6.48 (1 H, d), 6.41(1 H, s), 4.56-4.37 (2 H, m), 4.27 (2 H, t), 4.02 (1 H, dd), 3.95- 3.63(5 H, m), 3.61-3.45 (5 H, m), 3.09 (2 H, t), 2.14-1.99 (4 H, m) 75 (¹H,CDCl₃) δ ppm 7.70-7.57 (2 H, m), 7.47-7.20 (5 H, m), 7.05 (1 H, dd),6.96 (1 H, d), 6.27 (1 H, s), 5.26 (2 H, s), 4.47-4.32 (2 H, m),4.23-4.15 (2 H, m), 4.03-3.91 (1 H, m), 3.89-3.56 (5 H, m), 3.47 (1 H,dd), 2.97 (2 H, t) 76 (¹H, CDCl₃) δ ppm 7.67 (1 H, d), 7.05 (1 H, dd),6.96 (1 H, d), 6.75 (1 H, s), 6.31 (1 H, s), 5.18 (2 H, s), 4.53-4.34 (2H, m), 4.22 (2 H, t), 4.00 (1 H, m), 3.92- 3.62 (5 H, m), 3.50 (1 H,dd), 3.00 (2 H, t), 1.32 (9 H, s) 77 (¹H, CDCl₃) δ ppm 7.64 (1 H, d),7.00 (1 H, dd), 6.91 (1 H, d), 6.27 (1 H, s), 5.17 (2 H, s), 4.47-4.32(2 H, m), 4.23-4.14 (2 H, m), 3.96 (1 H, qd), 3.89-3.58 (5 H, m), 3.47(1 H, dd), 2.97 (2 H, t), 2.29-2.17 (1 H, m), 1.30-1.24(4 H, m) 78 (¹H,CDCl₃) δ ppm 7.65 (1 H, d), 7.01 (1 H, dd), 6.92 (1 H, d), 6.27 (1 H,s), 5.22 (2 H, s), 4.47-4.30 (2 H, m), 4.24-4.13 (2 H, m), 3.96 (1 H,m), 3.90-3.580 (5 H, m), 3.47 (1 H, dd), 3.02-2.85 (4 H, m), 1.41 (3 H,t) 79 (¹H, CDCl₃) δ ppm 7.68 (1 H, d), 7.05 (1 H, dd), 6.95 (1 H, d),6.32 (1 H, s), 5.26 (2 H, s), 4.52-4.37 (2 H, m), 4.28-4.20 (2 H, m),4.06-3.96 (1 H, m), 3.94-3.62 (5 H, m), 3.51 (1 H, dd), 3.02 (2 H, t),2.67 (3 H, s) 80 (¹H, CDCl₃) δ ppm 7.65 (1 H, d), 7.02 (1 H, dd), 6.93(1 H, d), 6.28 (1 H, s), 5.22 (2 H, s), 4.47-4.33 (2 H, m), 4.19 (2 H,t), 4.03-3.91 (1 H, m), 3.89-3.59 (5 H, m), 3.48 (1 H, dd), 3.26 (1 H,dt), 2.99 (2 H, t), 1.43 (6 H, d) 81 (¹H, CDCl₃) δ ppm 7.63 (1 H, d),7.40 (1 H, dd), 7.34 (1 H, s), 6.38 (1 H, s), 4.53- 4.37 (2 H, m),4.27-4.17 (2 H, m), 4.05-3.96 (1 H, m), 3.93-3.63 (5 H, m), 3.58- 3.46(1 H, m), 3.00 (2 H, t), 2.88 (1 H, m), 2.13-1.97 (2 H, m), 1.90-1.56 (6H, m) 82 (¹H, CDCl₃) δ ppm 7.64 (1 H, d), 7.41 (1 H, d), 7.35 (1 H, s),6.38 (1 H, s), 4.52- 4.36 (2 H, m), 4.22 (2 H, t), 4.01 (1 H, m),3.93-3.63 (5 H, m), 3.51 (1 H, t), 3.00 (2 H, t), 2.71-2.58 (1 H, m),1.99-1.31 (10 H, m) 83 (¹H, CDCl₃) δ ppm 7.64 (1 H, d), 7.40 (1 H, dd),7.35 (1 H, s), 6.38 (1 H, s), 4.49- 4.40 (2 H, m), 4.22 (2 H, t),4.05-3.97 (1 H, m), 3.91-3.65 (5 H, m), 3.51 (1 H, dd), 3.00 (2 H, t),2.88-2.78 (1 H, m), 1.31 (6 H, d) 84 (¹H, CDCl₃) δ ppm 7.64 (1 H, d),7.40 (1 H, dd), 7.35 (1 H, s), 6.38 (1 H, s), 4.51- 4.38 (2 H, m),4.26-4.18 (2 H, m), 4.07-3.97 (1 H, m), 3.93-3.64 (5 H, m), 3.52 (1 H,dd), 3.00 (2 H, t), 2.47 (2 H, t), 1.70-1.45 (4 H, m), 0.99 (3 H, t) 85(¹H, CDCl₃) δ ppm 7.65 (1 H, d), 7.45 (1 H, dd), 7.41-7.31 (5 H, m),7.27 (1 H, s), 6.37 (1 H, s), 4.49-4.34 (2 H, m), 4.24-4.17 (2 H, m),4.02-3.94 (1 H, m), 3.90-3.60 (7 H, m), 3.54 (2 H, s), 3.52-3.45 (1 H,m), 3.00 (2 H, t), 2.42 (3 H, s) 86 (¹H, CDCl₃) δ ppm 7.63 (1 H, d),7.42 (1 H, dd), 7.36 (1 H, s), 6.37 (1 H, s), 4.70- 4.65 (1 H, m),4.47-4.37 (2 H, m), 4.20 (2 H, t), 4.00-3.97 (1 H, m), 3.88-3.63 (5 H,m), 3.49 (1 H, t), 2.99 (2 H, t), 1.93-1.65 (4 H, m), 1.00-0.97 (6 H, m)87 (¹H, CDCl₃) δ ppm 7.63 (1 H, d), 7.42 (1 H, d), 7.36 (1 H, s), 6.37(1 H, s), 4.80- 4.77 (1 H, m), 4.46-4.37 (2 H, m), 4.20 (2 H, t),4.01-3.97 (1 H, m), 3.89-3.65 (5 H, m), 3.49 (1 H, t), 2.99 (2 H, t),1.99 (1 H, d), 1.57 (3 H, d) 88 (¹H, CDCl₃) δ ppm 7.60 (1 H, d), 7.07 (1H, d), 6.99 (1 H, s), 6.35 (1 H, s), 4.49- 4.38 (2 H, m), 4.21 (2 H, t),4.01 (1 H, m), 3.94-3.62 (5 H, m), 3.51 (1 H, t), 2.99 (2 H, t),2.07-1.86 (1 H, m), 1.15-1.06 (2 H, m), 0.85-0.78 (2 H, m) 89 (¹H,DMSO-d6) δ ppm 8.00 (1 H, d), 7.46 (1 H, s), 7.40 (1 H, d), 6.68 (1 H,s), 5.53 (1 H, d), 4.43-4.41 (1 H, m), 4.26-4.25 (2 H, m), 4.01 (2 H,t), 3.87-3.40 (7 H, m), 3.00 (2 H, t), 1.67-1.65 (2 H, m), 0.98 (3 H, t)90 (¹H, DMSO-d6) δ ppm 8.00 (1 H, d), 7.46 (1 H, s), 7.40 (1 H, d), 6.68(1 H, s), 5.53 (1 H, d), 4.28-4.25 (3 H, m), 4.01 (2 H, t), 3.85-3.38 (7H, m), 3.00 (2 H, t), 1.85-1.80 (1 H, m), 0.98 (6 H, t) 91 (¹H, DMSO-d6)δ ppm 8.00 (1 H, d), 7.44 (1 H, s), 7.38 (1 H, d), 6.68 (1 H, s), 5.27(1 H, S), 4.26-4.25 (2 H, m), 4.01 (2 H, t), 3.86-3.74 (3 H, m),3.67-3.60 (2 H, m) 3.52-3.46 (1 H, m), 3.37-3.35 (1 H, m), 3.00 (2 H,t), 1.66-1.62 (4 H, m), 0.99 (6 H, t) 92 (¹H, CDCl₃) δ ppm 7.71 (2 H,d), 7.66 (1 H, d), 7.47 (1 H, d), 7.43-7.32 (4 H, m), 6.38 (1 H, s),4.47-4.37 (2 H, m), 4.20 (2 H, t), 4.00-3.98 (1 H, m), 3.97-3.68 (5 H,m), 3.49 (1 H, t), 3.00 (2 H, t), 2.53 (1 H, s), 1.88 (3 H, s) 93 (¹H,CDCl₃) δ ppm 7.64 (1 H, d), 7.43-7.29 (7 H, m), 6.37 (1 H, s), 4.46-4.37(2 H, m), 4.21 (2 H, t), 3.99-3.95 (3 H, m), 3.88-3.63 (7 H, m), 3.49 (1H, t), 2.99 (2 H, t) 94 (¹H, CDCl₃) δ ppm 7.57-7.48 (1 H, d), 7.38 (1 H,s), 6.68-6.55 (1 H, d), 6.49 (1 H, s), 6.35 (1 H, s), 6.28 (1 H, s),6.20 (1 H, s), 4.60-4.50 (1 H, m), 4.38-4.30 (4 H, m), 4.22-4.15 (2 H,m), 4.03-3.93 (1 H, m), 3.95-3.60 (5 H, m), 3.55-3.40 (1 H, t),2.98-2.85 (2 H, m) 95 (¹H, CDCl₃) δ ppm 7.86 (1 H, s), 7.77 (1 H, s),7.70 (1 H, d), 7.51 (1 H, d), 7.42 (1 H, s), 6.39 (1 H, s), 4.51-4.37 (2H, m), 4.330-4.20 (4 H, m), 4.05-3.96 (1 H, m), 3.87 (5 H, s), 3.51 (1H, dd), 3.05 (2 H, t), 1.57 (4 H, t) 96 (¹H, CDCl₃) δ ppm 7.85 (1 H, s),7.75 (1 H, s), 7.70 (1 H, d), 7.50 (1 H, dd), 7.42 (1 H, s), 6.39 (1 H,s), 4.50-4.39 (2 H, m), 4.27-4.18 (4 H, m), 4.05-3.97 (1 H, m), 3.86 (5H, m), 3.51 (1 H, dd), 3.05 (2 H, t), 1.88-1.79 (2 H, m), 1.69-1.59 (1H, m), 1.00 (6 H, d) 97 (¹H, CDCl₃) δ ppm 8.03 (1 H, d), 7.67-7.63 (2 H,m), 7.05 (1 H, d), 6.65 (1 H, s), 6.28 (1 H, dd), 4.30-4.23 (2 H, m),4.04 (2 H, t), 3.89-3.75 (3 H, m), 3.63 (2 H, dd), 3.50 (1 H, d), 3.39(1 H, dd), 3.04 (2 H, t), 2.37 (3 H, s) 98 (¹H, CDCl₃) δ ppm 7.64 (1 H,d), 7.42 (1 H, d), 7.36 (1 H, s), 6.37 (1 H, s), 4.66- 4.61 (1 H, m),4.47-4.37 (2 H, t), 4.20 (2 H, t), 4.00-3.88 (1 H, m), 3.88-3.46 (5 H,m), 3.49 (1 H, t), 2.99 (2 H, t), 1.90-1.89 (1 H, m), 1.81-1.77 (2 H,m), 1.57-1.54 (2 H, m), 1.00 (3 H, t) 99 (¹H, CDCl₃) δ ppm 7.75 (1 H,d), 7.33-7.28 (1 H, m), 7.22 (1 H, s), 6.41 (1 H, s), 4.50-4.39 (2 H,m), 4.29-4.23 (2 H, m), 4.05-3.97 (1 H, m), 3.85 (5 H, m), 3.54- 3.47 (1H, m), 3.07 (2 H, d), 2.36 (6 H, s) 100 (¹H, CDCl₃) δ ppm 8.36 (1 H, br.s.), 8.07 (1 H, br. s.), 7.99 (1 H, d), 7.64-7.70 (2 H, m), 6.65 (1 H,s), 4.31-4.22 (2 H, m), 4.05 (2 H, t), 3.90-3.84 (1 H, m), 3.79 (2 H,td), 3.70-3.57 (2 H, m), 3.51-3.50 (1 H, m), 3.55-3.45 (1 H, m), 3.39 (1H, dd), 3.01 (2 H, t) 101 (¹H, CDCl₃) δ ppm 7.85 (1 H, d), 7.74 (1 H,d), 7.70 (1 H, d), 7.50 (1 H, dd), 7.44- 7.38 (1 H, m), 6.38 (1 H, s),4.48-4.348 (2 H, m), 4.27-4.17 (2 H, m), 4.15 (2 H, t), 4.04-3.96 (1 H,m), 3.90-3.64 (5 H, m), 3.50 (1 H, dd), 3.04 (2 H, t), 2.02- 1.90 (2 H,m), 0.97 (3 H, t) 102 (¹H, CDCl₃) δ ppm 7.91-7.80 (2 H, m), 7.71 (1 H,dd), 7.62-7.45 (4 H, m), 6.45 (1 H, s), 4.49-4.39 (2 H, m), 4.27 (2 H,t), 4.06-3.94 (1 H, m), 3.92-3.61 (5 H, m), 3.51 (1 H, dd), 3.11 (2 H,t) 103 (¹H, CDCl₃) δ ppm 7.80-7.90 (2 H, m), 7.79-7.69 (1 H, m),7.66-7.51 (4 H, m), 6.47 (1 H, s), 4.57-4.41 (2 H, m), 4.30 (2 H, t),4.03 (1 H, dt), 3.95-3.64 (5 H, m), 3.53 (1 H, t), 3.14 (2 H, t) 104(¹H, CDCl₃) δ ppm 7.65 (1 H, d), 7.01 (1 H, dd), 6.91 (1 H, d), 6.28 (1H, s), 5.18 (2 H, s), 4.47-4.35 (2 H, m), 4.24-4.15 (2 H, m), 4.02-3.93(1 H, m), 3.89- 3.61 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, t), 2.29-2.18(1 H, m), 1.33-1.20 (4 H, m) 105 (¹H, CDCl₃) δ ppm 7.65 (1 H, s),7.51-7.46 (1 H, m), 7.45-7.41 (1 H, m), 6.37 (1 H, s), 4.49-4.36 (2 H,m), 4.21 (2 H, s), 4.04-3.94 (1 H, m), 3.90-3.610 (5 H, m), 3.53-3.44 (1H, m), 3.25 (1 H, s), 3.00 (2 H, s) 106 (¹H, CDCl₃) δ ppm 9.18 (1 H, s),8.88 (2 H, s), 7.72 (1 H, d), 7.60-7.53 (1 H, m), 7.51 (1 H, d), 6.40 (1H, s), 4.49-4.36 (2 H, m), 4.23 (2 H, t), 4.02-3.95 (1 H, m), 3.89-3.58(5 H, m), 3.49 (1 H, dd), 3.04 (2 H, t) 107 (¹H, CDCl₃) δ ppm: 7.54 (1H, d), 7.37 (1 H, dd), 7.32 (1 H, s), 7.26-7.22 (2 H, m), 6.81 (1 H, t),6.75 (2 H, dd), 6.35 (1 H, s), 4.46-4.36 (2 H, m), 4.20-4.17 (4 H, m),4.00-3.91 (1 H, m), 3.88-3.63 (5 H, m), 3.49 (1 H, t), 2.97 (2 H, t) 108(¹H, CDCl₃) δ ppm 8.36 (1 H, d), 7.89-7.65 (3 H, m), 7.62-7.55 (3 H, m),6.44 (1 H, s), 4.51-4.38 (2 H, m), 4.26 (2 H, t), 4.00 (1 H, m),3.91-3.62 (5 H, m), 3.50 (1 H, dd), 3.22-3.14 (1 H, m), 3.09 (2 H, t),1.40 (1 H, t) 110 (¹H, CDCl₃) δ ppm 7.70-7.60 (1 H, d), 7.50-7.42 (1 H,d), 7.39 (1 H, s), 6.37 (1 H, s), 4.50-4.35 (2 H, m), 4.25-4.15 (2 H,m), 4.05-3.95 (2 H, m), 3.92-3.60 (5 H, m), 3.56-3.45 (4 H, m),3.05-3.95 (2 H, m), 2.15-1.95 (1 H, m), 1.15-1 (6 H, t) 111 (¹H, CDCl₃)δ ppm 7.58 (1 H, d), 7.33 (1 H, d), 7.27 (1 H, s), 6.32 (1 H, s), 4.45-4.34 (2 H, m), 4.17 (2 H, t), 3.96 (1 H, qd), 3.86-3.60 (5 H, m), 3.46(1 H, dd), 2.94 (2 H, t), 1.46 (1 H, tt), 0.94-0.86 (2 H, m), 0.86-0.79(2 H, m) 112 (¹H, CDCl₃) δ ppm 7.61 (1 H, d), 7.22 (1 H, d), 7.14 (1 H,s), 6.34 (1 H, s), 4.48- 4.34 (2 H, m), 4.19 (2 H, t), 4.02-3.93 (1 H,m), 3.89-3.60 (5 H, m), 3.48 (1 H, t), 3.43-3.35 (1 H, m), 2.98 (2 H,t), 2.95-2.85 (1 H, m), 2.76-2.64 (1 H, m), 1.84-1.62 (3 H, m), 0.92 (6H, dd) 113 (¹H, CDCl₃) δ ppm 7.67 (1 H, d), 7.44 (1 H, d), 7.39 (1 H,s), 6.38 (1 H, s), 5.00 (2 H, s), 4.50-4.36 (2 H, m), 4.21 (2 H, t),4.03-3.95 (1 H, m), 3.91-3.61 (5 H, m), 3.49 (1 H, dd), 3.01 (2 H, t)114 (¹H, CDCl₃) δ ppm 7.64-7.58 (1 H, m), 7.24-7.19 (1 H, m), 7.13 (1 H,s), 6.35 (1 H, s), 4.49-4.36 (2 H, m), 4.25-4.17 (2 H, m), 4.03-3.95 (1H, m), 3.90- 3.61 (5 H, m), 3.54-3.45(1 H, m), 3.02-2.95 (2 H, m),2.81-2.72 (2 H, m), 1.59- 1.49 (2 H, m), 0.77-0.64 (1 H, m), 0.49-0.42(2 H, m), 0.10-0.02 (2 H, m) 115 (¹H, CDCl₃) δ ppm 7.66 (1 H, d), 7.33(1 H, d), 7.29 (1 H, s), 6.36 (1 H, s), 4.50 (2 H, s), 4.47-4.35(2 H,m), 4.19 (2 H, t), 4.07-3.93 (2 H, m), 3.90-3.60 (5 H, m), 3.48 (1 H,t), 3.00 (2 H, t), 1.82-1.70 (6 H, m), 1.62-1.50 (2 H, m) 117 (¹H,CDCl₃) δ ppm 7.64 (1 H, d), 6.91 (1 H, dd), 6.80 (1 H, s), 6.28 (1 H,s), 6.11- 6.01 (1 H, m), 5.45 (1 H, dd), 5.34 (1 H, dd), 4.61 (2 H, dd),4.47-4.37 (2 H, m), 4.21 (2 H, t), 4.03-3.95 (1 H, m), 3.89-3.64 (5 H,m), 3.49 (1 H, t), 2.98 (2 H, t) 118 (¹H, CDCl₃) δ ppm 7.63 (1 H, d),6.91 (1 H, dd), 6.80 (1 H, d), 6.28 (1 H, s), 6.11- 6.01 (1 H, m), 5.44(1 H, m), 5.34 (1 H, dd), 4.61 (2 H, dt), 4.47-4.37 (2 H, m), 4.21 (2 H,t), 4.03-3.95 (1 H, m), 3.89-3.63 (5 H, m), 3.49 (1 H, dd), 2.98 (2 H,t) 119 (¹H, CDCl₃) δ ppm 7.68 (1 H, d), 7.36 (1 H, d), 7.31 (1 H, s),6.41-6.38 (1 H, m), 4.61 (2 H, s), 4.47-4.37 (2 H, m), 4.25-4.17 (2 H,m), 3.99 (3 H, dt), 3.89-3.60 (6 H, m), 3.53-3.43 (3 H, m), 3.02 (2 H,t), 2.01-1.94 (2 H, m), 1.74-1.64 (2 H, m) 120 (¹H, CDCl₃) δ ppm 8.62 (1H, br. s.), 8.53 (1 H, br. s.), 7.73 (1 H, d), 7.64 (1 H, d), 7.41 (1 H,dd), 7.35 (1 H, s), 7.29 (1 H, d), 6.36 (1 H, s), 4.48-4.34 (2 H, m),4.20 (2 H, t), 4.03-3.93 (3 H, m), 3.89-3.61 (7 H, m), 3.48 (1 H, dd),2.99 (2 H, t) 121 (¹H, CDCl₃) δ ppm 7.60 (1 H, d), 7.19 (1 H, dd), 7.10(1 H, s), 6.34 (1 H, s), 4.49- 4.34 (2 H, m), 4.20 (2 H, t), 4.02-3.93(1 H, m), 3.90-3.60 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, t), 2.64 (2 H,t), 1.63 (2 H, m), 1.37-1.29 (4 H, m), 0.94-0.86 (3 H, m) 122 (¹H,CDCl₃) δ ppm 7.63 (1 H, d), 7.39 (1 H, dd), 7.31 (1 H, s), 6.36 (1 H,s), 4.50- 4.39 (2 H, m), 4.20 (2 H, t), 4.02-3.98 (1 H, m), 3.89-3.66 (5H, m), 3.49 (1 H, t), 2.96 (2 H, t), 1.59-1.48 (1 H, m), 0.98-0.81 (4 H,m) 123 (¹H, CDCl₃) δ ppm 7.64-7.58 (1 H, m), 7.24-7.19 (1 H, m), 7.13 (1H, s), 6.35 (1 H, s), 4.49-4.36 (2 H, m), 4.24-4.17 (2 H, m), 4.03-3.95(1 H, m), 3.91- 3.62 (5 H, m), 3.49 (1 H, dd), 3.03-2.95 (2 H, m),2.81-2.73 (2 H, m), 1.59- 1.50 (2 H, m), 0.71 (1 H, s), 0.49-0.42 (2 H,m), 0.09-0.03 (2 H, m) 124 (¹H, CDCl₃) δ ppm 7.69 (1 H, d), 7.35 (1 H,d), 7.30 (1 H, s), 6.38 (1 H, s), 4.82- 4.75 (2 H, m), 4.72-4.64 (3 H,m), 4.49 (2 H, s), 4.48-4.37 (2 H, m), 4.21 (2 H, dd), 4.03-3.95 (1 H,m), 3.90-3.62 (5 H, m), 3.49 (1 H, dd), 3.02 (2 H, t) 125 (¹H, CDCl₃) δppm 7.69 (1 H, d), 7.35 (1 H, d), 7.29 (1 H, s), 6.38 (1 H, s), 4.62 (2H, s), 4.54 (2 H, d), 4.48-4.36 (4 H, m), 4.21 (2 H, t), 3.99 (1 H,ddt), 3.90-3.61 (5 H, m), 3.58 (2 H, s), 3.49 (1 H, dd), 3.02 (2 H, t),1.36 (3 H, s) 126 (¹H, CDCl₃) δ ppm 7.50 (1 H, d), 6.63 (1 H, dd), 6.48(1 H, s), 6.21 (1 H, s), 4.47- 4.34 (2 H, m), 4.21-4.14 (2 H, m),4.01-3.91 (1 H, m), 3.89-3.60 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, s),2.90 (2 H, t), 1.36 (2 H, dd), 0.96 (6 H, s), 0.87 (3 H, t) 127 (¹H,CDCl₃) δ ppm 7.61 (1 H, d), 7.22 (1 H, d), 7.14 (1 H, s), 6.34 (1 H, d),4.46- 4.34 (2 H, m), 4.19 (2 H, t), 3.97 (1 H, td), 3.89-3.60 (5 H, m),3.48 (1 H, t), 3.42- 3.35 (1 H, m), 2.97 (2 H, t), 2.93-2.85 (2 H, m),2.70 (1 H, m), 1.84-1.63 (3 H, m), 0.92 (6 H, dd) 128 (¹H, CDCl₃) δ ppm7.51 (1 H, d), 6.63 (1 H, d), 6.49 (1 H, br. s.), 6.21 (1 H, s),4.46-4.356 (2 H, m), 4.21-4.11 (2 H, m), 3.97 (1 H, ddt), 3.88-3.62 (5H, m), 3.48 (1 H, dd), 3.10 (2 H, d), 2.91 (2 H, t), 1.61 (1 H, m),1.47-1.26 (8 H, m), 0.97-0.88 (6 H, m) 129 (¹H, CDCl₃) δ ppm 7.63 (1 H,d), 6.93 (1 H, dd), 6.82 (1 H, d), 6.29 (1 H, s), 5.30 (1 H, s),4.47-4.36 (2 H, m), 4.22-4.14 (4 H, m), 4.03-3.94 (1 H, m), 3.88- 3.628(7 H, m), 3.53-3.453 (4 H, m), 2.97 (2 H, t) 130 (¹H, CDCl₃) δ ppm7.64-7.58 (1 H, m), 6.90 (1 H, dd), 6.80 (1 H, d), 6.29-6.24 (1 H, m),4.46-4.32 (2 H, m), 4.22-4.12 (4 H, m), 4.01-3.90 (1 H, m), 3.88- 3.54(9 H, m), 3.46 (1 H, dd), 2.95 (2 H, s), 1.23 (3 H, t) 131 (¹H, CDCl₃) δppm 7.60-7.67 (1 H, m), 6.93-6.86 (1 H, m), 6.78 (1 H, d), 6.29 (1 H,s), 4.50-4.36 (2 H, m), 4.25-4.17 (2 H, m), 4.04-3.94 (1 H, m), 3.91-3.61 (7 H, m), 3.53-3.44 (1 H, m), 3.01-2.93 (2 H, m), 1.37-1.227 (1 H,m), 0.73-0.65 (2 H, m), 0.42-0.34 (2 H, m) 132 (¹H, CDCl₃) δ ppm 7.64 (1H, d), 6.93 (1 H, s), 6.82 (1 H, d), 6.27 (1 H, s), 4.90- 4.82 (1 H, m),4.74-4.67 (1 H, m), 4.48-4.28 (3 H, m), 4.26-4.14 (3 H, m), 4.03- 3.91(1 H, m), 3.90-3.58 (5 H, m), 3.53-3.41 (1 H, m), 3.03-2.91 (2 H, m) 133(¹H, CDCl₃) δ ppm 7.64 (1 H, s), 7.48-7.40 (1 H, m), 7.40-7.35 (1 H, m),6.40- 6.34 (1 H, m), 4.47 (4 H, s), 4.28-4.15 (1 H, m), 3.93-3.56 (10 H,m), 3.43 (5 H, s), 3.06-2.95 (2 H, m) 134 (¹H, CDCl₃) δ ppm 7.65 (1 H,d), 7.47-7.41 (1 H, m), 7.38 (1 H, s), 6.37 (1 H, s), 4.37-4.49 (4 H,m), 4.26-4.17 (2 H, m), 3.99 (1 H, m), 3.93-3.44 (12 H, m), 3.05-2.94 (2H, m), 1.25 (3 H, t) 135 (¹H, CDCl₃) δ ppm 7.66 (1 H, d), 7.47-7.42 (1H, m), 7.40 (1 H, s), 6.37 (1 H, s), 4.73-4.67 (1 H, m), 4.62-4.54 (1 H,m), 4.49 (4 H, s), 4.26-4.16 (2 H, m), 4.04- 3.95 (1 H, m), 3.94-3.60 (7H, m), 3.56-3.43 (1 H, m), 3.05-2.96 (2 H, m) 136 (¹H, CDCl₃) δ ppm 7.68(1 H, d), 7.35 (1 H, d), 7.30 (1 H, s), 6.38 (1 H, s), 4.57 (2 H, s),4.50-4.36 (2 H, m), 4.27-4.17 (2 H, m), 4.06-3.92 (1 H, m), 3.92-3.60 (5H, m), 3.57-3.44 (1 H, m), 3.17 (2 H, s), 3.09-2.96 (2 H, m), 0.97 (9 H,s) 137 (¹H, CDCl₃) δ ppm 7.70-7.64 (1 H, m), 7.40-7.33 (1 H, m), 7.31 (1H, s), 6.37 (1 H, s), 4.59 (2 H, s), 4.50-4.35 (2 H, m), 4.27-4.16 (2 H,m), 4.07-3.94 (1 H, m), 3.93-3.59 (5 H, m), 3.57-3.44 (1 H, m),3.45-3.34 (1 H, m), 3.08-2.96 (2 H, m), 2.05-1.90 (2 H, m), 1.82-1.71 (2H, m), 1.48-1.18 (6 H, m) 138 (¹H, CDCl₃) δ ppm 7.68 (1 H, d), 7.37 (1H, d), 7.32 (1 H, s), 6.38 (1 H, s), 4.58 (2 H, s), 4.51-4.36 (2 H, m),4.26-4.176 (2 H, m), 4.05-3.94 (1 H, m), 3.92-3.61 (5 H, m), 3.54-3.44(1 H, m), 3.38 (2 H, d), 3.07-2.98 (2 H, m), 1.20-1.05 (1 H, m),0.63-0.54 (2 H, m), 0.29-0.20 (2 H, m) 139 (¹H, CDCl₃) δ ppm 7.62 (1 H,s), 6.91 (1 H, m), 6.81 (1 H, m), 6.27 (1 H, s), 4.41 (2 H, s),4.25-4.21 (2 H, m), 4.10-3.41 (12 H, m), 2.96 (2 H, t), 2.01-1.84 (1 H,m), 1.76-1.36 (5 H, m) 140 (¹H, DMSO-d₆) δ□ppm 7.91 (1 H, d), 7.28-7.18(2 H, m), 6.60 (1 H, s), 4.32- 4.17 (2 H, m), 4.07-3.96 (2 H, m),3.92-3.71 (3 H, m), 3.70-3.43 (4 H, m), 3.38 (2 H, m), 3.03-2.91 (2 H,m), 2.78-2.58 (2 H, m), 1.68-1.58 (2 H, m), 1.08 (3 H, d) 141 (¹H,CDCl₃) δ ppm 7.70-7.58 (1 H, d), 6.95-6.82 (1 H, d), 6.77 (1 H, s), 6.27(1 H, s), 4.50-4.32 (2 H, m), 4.38-4.15 (2 H, m), 4.05-3.92 (3 H, m),3.92-3.60 (5 H, m), 3.55-3.42 (1 H, t), 3.05-2.92 (2 H, m), 1.85-1.70 (2H, m), 1.40- 1.30 (2 H, m), 0.92 (9 H, s) 142 (¹H, CDCl₃) δ ppm 7.61 (1H, d), 7.21 (1 H, d), 7.13 (1 H, s) 6.35 (1 H, s), 4.46- 4.40 (2 H, m),4.20 (2 H, t), 3.99-3.97 (1 H, m), 3.87-3.65 (5 H, m), 3.49(1 H, t),3.39 (3 H, s), 3.00-2.93 (3 H, m), 2.83-2.82 (1 H, m), 2.66-2.64 (1 H,m), 1.95-1.91 (1 H, m), 1.75-1.73 (2 H, m), 0.90 (6 H, t) 143 (¹H,CDCl₃) δ ppm 7.66-7.60 (1 H, m), 6.91-6.86 (1 H, m), 6.80-6.76 (1 H, m),6.28 (1 H, s), 4.48-4.35 (2 H, m), 4.24-4.17 (2 H, m), 4.11-4.04 (2 H,m), 4.02- 3.95 (1 H, m), 3.91-3.61 (5 H, m), 3.54-3.45 (1 H, m),3.03-2.94 (2 H, m), 1.98-1.88 (2 H, m), 1.45-1.36 (2 H, m), 0.78-0.66 (1H, m), 0.50-0.43 (2 H, m), 0.09-0.03 (2 H, m) 145 (¹H, CDCl₃) δ ppm 7.47(1 H, d), 6.55-6.48 (1 H, m), 6.40-6.34 (1 H, m), 6.18 (1 H, s),4.47-4.33 (2 H, m), 4.22-4.12 (2 H, m), 4.02-3.92 (1 H, m), 3.83 (5 H,dd), 3.53-3.43 (1 H, m), 3.40-3.28 (1 H, m), 2.89 (2 H, t), 2.13-1.98 (2H, m), 1.86-1.73 (2 H, m), 1.73-1.63 (1 H, m), 1.50-1.11 (5 H, m) 146(¹H, DMSO-d₆) δ □ppm 7.95-7.87 (1 H, m), 7.29-7.19 (2 H, m), 6.60 (1 H,s), 4.54-4.44 (1 H, m), 4.29-4.21 (2 H, m), 4.07-3.97 (2 H, m),3.91-3.72 (3 H, m), 3.70-3.54 (2 H, m), 3.54-3.43 (1 H, m), 3.43-3.34(1H, m), 3.06-2.81 (4 H, m), 2.63-2.52 (1 H, m), 1.81-1.64 (1 H, m),1.52-1.36 (1 H, m), 0.81 (9 H, s) 147 (¹H, CDCl₃) δ ppm 7.68 (1 H, d),7.38-7.32 (1 H, m), 7.30 (1 H, s), 6.38 (1 H, s), 4.56 (2 H, s),4.50-4.36 (2 H, m), 4.26-4.18 (2 H, m), 4.04-3.94 (1 H, m), 3.94- 3.5994(4 H, m), 3.55-3.44 (1 H, m), 3.40 (2 H, d), 3.07-2.98 (2 H, m), 2.30-2.16 (1 H, m), 1.86-1.72 (2 H, m), 1.66-1.51 (5 H, m), 1.35-1.20 (2 H,m) 148 (¹H, CDCl₃) δ ppm 7.61 (1 H, d), 7.18 (1 H, dd), 7.12 (1 H, d),6.35 (1 H, s), 4.46- 4.36 (2 H, m), 4.21 (2 H, t), 4.00-3.97 (1 H, m),3.88-3.64 (5 H, m), 3.49 (1 H, t), 3.34-3.30 (4 H, m), 2.98 (2 H, t),2.81-2.60 (2 H, m), 1.89-1.676 (2 H, m), 1.18 (3 H, d) 149 (¹H, CDCl₃) δppm: 7.62 (1 H, d), 7.23-7.13 (4 H, m), 6.71 (1 H, t), 6.58 (2 H, d),6.12 (1 H, s), 4.47-4.37 (2 H, m), 4.21 (2 H, t), 4.08-3.98 (1 H, m),3.88-3.63 (6 H, m), 3.49 (1 H, t), 3.17 (2 H, t), 2.98 (2 H, t), 2.79 (2H, t), 2.01-1.94 (2 H, m) 150 (¹H, CDCl₃) δ ppm 7.61 (1 H, d), 7.20 (1H, d), 7.12 (1 H, s), 6.35 (1 H, s), 4.47- 4.37 (2 H, m), 4.21 (2 H, t),4.01-3.97 (1 H, m), 3.88-3.63 (6 H, m), 3.49 (1 H, t), 2.98 (2 H, t),2.69 (2 H, t), 1.89-1.62 (2 H, m), 1.52-1.45 (2 H, m), 1.31- 1.30 (1 H,m), 1.20 (3 H, d) 151 (¹H, CDCl₃) δ ppm 7.61 (1 H, d), 7.20 (1 H, d),7.12 (1 H, s), 6.35 (1 H, s), 4.47- 4.37 (2 H, m), 4.21 (2 H, t),4.01-3.97 (1 H, m), 3.88-3.63 (7 H, m), 3.49 (1 H, t), 2.98 (2 H, t),2.70 (2 H, t), 1.76-1.60 (4 H, m), 1.31-1.26 (1 H, m) 152 (¹H, CDCl₃) δppm 7.57-7.50 (1 H, m), 6.71 (1 H, d), 6.53 (1 H, br. s.), 6.21 (1 H,s), 4.513-4.33 (2 H, m), 4.26-4.14 (2 H, m), 4.06-3.93 (1 H, m),3.92-3.56 (6 H, m), 3.56-3.41 (1 H, m), 3.00-2.90 (2 H, m), 2.88 (3 H,s), 2.04-1.63 (2 H, m), 1.60-1.31 (5 H, m), 1.28-1.08 (1 H, m) 153 (¹H,CDCl₃) δ ppm 7.52-7.46 (1 H, m), 6.55-6.50 (1 H, m), 6.40-6.36 (1 H, m),6.19 (1 H, s), 4.48-4.33 (2 H, m), 4.23-4.13 (2 H, m), 4.04-3.92 (1 H,m), 3.85 (5 H, d), 3.56-3.42 (1 H, m), 3.06-2.99 (2 H, m), 2.93-2.84 (2H, m), 1.92- 1.50 (6 H, m), 1.36-1.12 (3 H, m), 1.08-0.91 (2 H, m) 154(¹H, CDCl₃) δ ppm 7.50 (1 H, d), 6.59-6.49 (1 H, m), 6.44-6.35 (1 H, m),6.20 (1 H, s), 4.49-4.33 (2 H, m), 4.24-4.13 (2 H, m), 4.05-3.93 (3 H,m), 3.92- 3.59 (5 H, m), 3.56-3.32 (3 H, m), 3.16-3.07 (2 H, m),2.96-2.84 (2 H, m), 1.98- 1.80 (1 H, m), 1.79-1.64 (2 H, m), 1.428-1.28(2 H, m) 155 (¹H, CDCl₃) δ ppm 7.54-7.46 (1 H, m), 7.14-7.08 (1 H, m),7.04 (1 H, s), 6.23 (1 H, s), 4.35-4.21 (2 H, m), 4.13-3.99 (2 H, m),3.91-3.80 (1 H, m), 3.79- 3.45 (5 H, m), 3.41-3.30 (1 H, m), 2.86 (2 H,t), 2.64-2.54 (2 H, m), 1.67-1.58 (2 H, m), 1.45 (4 H, d), 0.80 (6 H, m)156 (¹H, CDCl₃) δ ppm 7.60 (1 H, d), 7.23-7.19 (1 H, m), 7.13 (1 H, s),6.34 (1 H, s), 4.45-4.35 (2 H, m), 4.18 (2 H, t), 4.02-3.92 (1 H, m),3.82 (5 H, m), 3.48 (1 H, dd), 2.97 (2 H, br. t), 2.79-2.70 (2 H, m),1.82-1.74 (2 H, m), 1.30 (6 H, s) 157 (¹H, CDCl₃) δ ppm 7.64-7.59 (1 H,m), 7.25-7.20 (1 H, m), 7.14 (1 H, s), 6.35 (1 H, s), 4.48-4.35 (2 H,m), 4.24-4.16 (2 H, m), 4.02-3.94 (1 H, m), 3.90- 3.44 (7 H, m),3.02-2.95 (2 H, m), 2.92-2.81 (1 H, m), 2.78-2.67 (1 H, m), 1.87- 1.68(2 H, m), 1.62-1.42 (2 H, m), 0.96 (3 H, s) 158 (¹H, CDCl₃) δ ppm7.70-7.56 (1 H, d), 6.95-6.85 (1 H, d), 6.80 (1 H, s), 6.28 (1 H, s),4.50-4.35 (2 H, m), 4.25-4.10 (2 H, m), 4.05-3.92 (1 H, m), 3.10-3.57 (8H, m), 3.55-3.40 (1 H, m), 3.05-2.90 (2 H, m), 1.05 (9H, s) 159 (¹H,CDCl₃) δ ppm 7.63 (1 H, d), 6.88 (1 H, dd), 6.77 (1H, d), 6.28 (1 H, s),4.46- 4.36 (2 H, m), 4.20 (2 H, t), 4.05-3.96 (3 H, m), 3.88-3.65 (7 H,m), 3.51-3.43 (3 H, m), 2.97 (2 H, t), 2.12-2.01 (1 H, m), 1.78-1.75 (2H, m), 1.59-1.42 (2 H, m) 160 (¹H, CDCl₃) δ ppm 7.63 (1 H, d), 7.35-7.18(1 H, m), 7.12 (1H, s), 6.36 (1 H, s), 4.50-4.35 (2 H, m), 4.28-4.15 (2H, m), 4.05-3.95 (1 H, m), 3.95-3.60 (5 H, m), 3.55-3.42 (1 H, m),3.05-2.90 (2 H, m), 2.75-2.60 (2 H, m), 1.80-1.65 (2 H, m), 1.55-1.48 (2H, m), 1.22 (6 H, s) 161 (¹H, CDCl₃) δ ppm 7.68 (1 H, d), 7.34 (1 H, d),7.29 (1 H, s), 6.38 (1 H, s), 4.55 (2 H, s), 4.48-4.38 (2 H, m), 4.22 (2H, t), 4.02-3.96 (3 H, m), 3.91-3.61 (5 H, m), 3.55-3.35 (5 H, m), 3.02(2 H, t), 2.00-1.86 (1 H, m), 1.69 (2 H, dd), 1.38 (2 H, dd) 162 (¹H,CDCl₃) δ ppm 7.68-7.62 (1 H, m), 6.95-6.87 (1 H, m), 6.82-6.77 (1 H, m),6.29 (1 H, s), 4.51-4.35 (2 H, m), 4.26-4.17 (2 H, m), 4.05-3.92 (1 H,m), 3.91- 3.60 (8 H, m), 3.55-3.44 (1 H, m), 3.04-2.94 (2 H, m) 163 (¹H,CDCl₃) δ ppm 7.64 (1 H, d), 6.91 (1 H, dd), 6.81 (1 H, d), 6.29 (1H, s),4.91 (2 H, t), 4.56 (2 H, t), 4.47-4.36 (2 H, m), 4.26 (2H, d), 4.21 (2H, t), 4.00-3.96 (1 H, m), 3.88-3.63 (5 H, m), 3.51-3.45 (2 H, m), 2.98(2H, t) 164 (¹H, DMSO-d₆) δ □ppm 7.93 (1 H, d), 6.97-6.92 (2 H, m), 6.53(1 H, s), 4.24- 4.23 (2H, m), 4.08 (2 H, t), 4.00 (2 H, t), 3.98-3.74 (3H, m), 3.68-3.57 (2 H, m), 3.51-3.48 (1 H, m), 3.37 (1 H, t), 2.96 (2 H,t), 1.84-1.80 (2 H, m), 1.36- 1.30 (2 H, m), 0.81-0.63 (1 H, m),0.42-0.39 (2 H, m), 0.04-0.02 (2 H, m) 165 (¹H, CDCl₃) δ ppm 7.65 (1 H,d), 7.24 (1H, dd), 7.16 (1H, s), 6.38 (1 H, s), 4.49- 4.40 (2 H, m),4.24 (2 H, t), 4.02-4.00 (1 H, m), 3.89-3.66 (3 H, m), 3.52 (3 H, m),3.43 (2 H, t), 3.38 (3 H, s), 3.02 (2H, t), 2.78 (2 H, t), 1.96-1.92 (2H, m) 166 (¹H, CDCl₃) δ ppm 7.61 (1 H, d), 7.23 (1H, dd), 7.15 (1H, s),6.35 (1 H, s), 4.46- 4.36 (2 H, m), 4.20 (2 H, t), 4.01-3.95 (1 H, m),3.88-3.62 (5 H, m), 3.49 (1 H, t), 2.98 (2 H, t), 2.85-2.81 (2 H, m),2.13 (1H, br s), 1.93-1.79 (4 H, m), 1.72- 1.55 (6 H, m) 167 (¹H, CDCl₃)δ ppm 7.59 (1 H, d), 7.37 (1H, dd), 7.15 (1H, s), 6.34 (1 H, s), 4.44-4.35 (2 H, m), 4.17 (2 H, t), 4.01-3.92 (3 H, m), 3.88-3.60 (7 H, m),3.47 (1 H, t), 2.94 (2 H, t), 2.07-2.02 (2 H, m), 1.95-1.88 (2H, m) 168(¹H, CDCl₃) δ ppm 7.66 (1 H, d), 7.23 (1H, dd), 7.17 (1H, s), 6.39 (1 H,s), 4.51- 4.40 (2 H, m), 4.24 (2 H, t), 4.09-3.96 (1 H, m), 3.93-3.65 (5H, m), 3.57-3.49 (1H, m), 3.44 (2 H, t), 3.40 (3H, s), 3.02 (2 H, t),2.79 (2 H, t), 2.00-1.89 (2H, m) 169 (¹H, CDCl₃) δ ppm 7.55 (1 H, d),7.16 (1H, dd), 7.08 (1H, s), 6.29 (1 H, s), 4.41- 4.29 (2 H, m), 4.13 (2H, t), 3.95-3.86 (1 H, m), 3.81-3.54 (5 H, m), 3.46-3.38 (1H, m), 2.91(2 H, t), 2.78-2.72 (2H, m), 1.87-1.75 (4 H, m), 1.72-1.53 (6 H, m) 170(¹H, CDCl₃) δ ppm 7.66 (1 H, d), 6.95 (1H, dd), 6.84 (1H, s), 6.31 (1 H,s), 4.50- 4.39 (2 H, m), 4.25-4.21 (4 H, m), 4.05-3.98 (1 H, m),3.91-3.65 (7 H, m), 3.55- 3.49 (3H, m), 3.00 (2 H, t), 1.71-1.62 (2 H,m), 0.96 (3 H, t) 171 (¹H, CDCl₃) δ ppm 7.65 (1 H, d), 6.94 (1H, dd),6.83 (1H, s), 6.31 (1 H, s), 4.50- 4.39 (2 H, m), 4.25-4.18 (4 H, m),4.04-3.97 (1 H, m), 3.91-3.65 (8 H, m), 3.51 (1H, t), 3.00 (2 H, t),1.23 (6 H, d) 172 (¹H, CDCl₃) δ ppm 7.67 (1 H, d), 6.95 (1H, dd), 6.85(1H, s), 6.31 (1 H, s), 4.50- 4.40 (2 H, m), 4.25-4.21 (4 H, m),4.05-3.98 (1 H, m), 3.91-3.65 (7 H, m), 3.55- 3.49 (3H, m), 3.00 (2 H,t), 1.72-1.62 (2 H, m), 0.97 (3 H, t) 173 (¹H, CDCl₃) δ ppm 7.65 (1 H,d), 6.94 (1H, dd), 6.84 (1H, s), 6.31 (1 H, s), 4.50- 4.40 (2 H, m),4.26-4.19 (4 H, m), 4.04-3.97 (1 H, m), 3.92-3.65 (8 H, m), 3.52 (1H,t), 3.00 (2 H, t), 1.23 (6 H, d) 174 (¹H, CDCl₃) δ ppm 7.64 (1 H, d),7.22 (1H, dd), 7.15 (1H, s), 6.38 (1 H, s), 4.51- 4.41 (2 H, m), 4.23 (2H, t), 4.06-4.00 (1 H, m), 3.92-3.66 (5 H, m), 3.57-3.50 (1H, m), 3.43(2 H, t), 3.37 (3H, s), 3.01 (2 H, t), 2.71 (2 H, t), 1.80-1.61 (2H, m),1.69-1.62 (2H, m)

BIOLOGICAL EXAMPLES

1. In vitro Assays

1.1. Cell Based Assay: GTp-γ S Binding Assay.

The following assay can be used for determination of GPR84 activation.The [³⁵S]GTPγS binding assay measures the level of G protein activationfollowing agonist occupation of a GPCR, by determining the binding ofthe non-hydrolysable analog [³⁵S]GTPγS to Gα subunits.

The assay is performed in a 96 well plate where the following reagentsare added. First 50 μL compound is added into the assay plate, followedby addition of 20 μL 3,3′ di indolylmethane at EC₈₀ concentration(concentration which gives 80% of the activity of GPR84). In a laststep, 30 μL of a mixture consisting of membranes-GTPγS-SpA beads isadded [mixture consists of 20 μg/well membranes derived from stable cellline over expressing GPR84 (membranes are pre-incubated with 0.1 μM GDPfor 15 min at 4° C.), 0.1 nM [³⁵S]GTPγS (Perkin Elmer, NEG030) and 0.5mg/well PVT-WGA SpA beads (Perkin Elmer, RPNQ0001)]. All components arediluted in assay buffer containing 20 mM HEPES pH 7.4; 5 mM MgCl₂; 250mM NaCl; 0.05% BSA; 75 ug/mL saponin. Reactions are incubated for 90 minat room temperature followed by centrifugation at 2000 rpm during 15min. Plates are read on a Topcount reader (Perkin Elmer) immediatelyafter centrifugation (readout time, 1 min/well).

TABLE IV GPR84 assay GTPγS IC₅₀ (nM) of selected Compounds of theinvention. Cpd# GPR84 1 *** 3 ** 4 *** 5 ** 6 *** 7 *** 8 *** 9 **** 16*** 20 **** 28 ** 30 **** 36 **** 41 *** 42 *** 43 *** 45 ** 50 *** 51*** 52 **** 53 *** 54 *** 55 * 56 *** 57 *** 58 *** 59 ** 60 **** 61**** 62 **** 63 *** 64 *** 65 ** 66 *** 67 **** 68 **** 69 **** 70 ****72 **** 74 **** 75 **** 76 **** 77 **** 78 **** 79 *** 80 **** 81 ****82 **** 83 **** 84 **** 85 **** 86 **** 87 *** 89 *** 90 **** 91 *** 93**** 94 **** 95 ** 96 *** 97 *** 98 **** 101 *** 102 *** 103 *** 104**** 105 *** 106 ** 107 **** 108 **** 109 **** 110 *** 111 *** 112 ****113 *** 114 **** 115 **** 116 *** 117 *** 118 *** 119 *** 120 *** 121**** 122 **** 123 **** 124 *** 125 ** 126 **** 127 **** 128 *** 129 ***130 *** 131 **** 132 ** 133 *** 134 *** 135 *** 136 **** 137 **** 138**** 139 **** 140 *** 141 *** 142 **** 145 *** 146 **** 147 **** 148**** 149 **** 150 *** 151 *** 152 ** 153 *** 154 ** 155 **** 156 *** 157*** 158 *** 159 **** 160 *** 161 *** 162 *** 163 **** 164 **** 165 ****166 **** 167 ** 168 *** 169 *** 170 **** 171 **** 172 *** 173 ** 174**** na: not active * >1001 nM ** 501-1000 nM *** 101-500 nM ****0.01-100 nM2. Cellular Assays

2.1. Human Neutrophil Migration Assay

We have established that GPR84 agonists (MCFA such as sodiumdecanoate,3,3′ di indolylmethane and Embelin induce neutrophil chemo taxis andthat GPR84 antagonists could block GPR84 agonist-induced chemo taxis butnot IL8-induced chemotaxis, indicating that G Protein-Coupled Receptor84 (GPR84) is an essential player in the process of neutrophilrecruitment.

The effect of agonists or antagonists for GPR84 can therefore be assayedin a neutrophil migration test. In the neutrophil migration assay,neutrophils, freshly isolated from buffy coats from human volunteers,are treated with a compound for 30 minutes. Subsequently, theneutrophils are transferred to the upper wells of a Corning HTStranswell 96 permeable support system, of which the lower wells arefilled with a embelin solution at EC₈₀ (concentration which gives 80% ofthe activity of GPR84). After 1 h of incubation, migration of theneutrophils towards embelin in the lower compartment can be quantifiedby measuring the ATP-content of the lower wells using the ATPliteluminescence ATP detection assay system (Perkin Elmer, Cat. No.:436110).

2.1.1 Isolation of Neutrophils from Human Buffy Coat

A human buffy coat is diluted with an equal volume of ice cold DPBS. 20mL of the diluted buffy coat is gently mixed with 4 mL of ACD buffer(140 mM citric acid, 200 mM sodium citrate and 220 mM dextrose). Then,12 mL of the 6% dextran/0.9% NaCl solution (15 g dextran T2000 and 2.25g NaCl dissolved in 250 mL H₂O) is added to the mixture and the samplesare inverted gently up to 20 times. The total volume was transferred toa new recipient and incubated at room temperature for 1 h for completeseparation of the two phases to occur. The yellowish supernatant is thentransferred to a clean centrifugation tube and centrifuged for 12minutes at 1300 rpm and 4° C. After centrifugation, the supernatant isdiscarded and the remaining cell pellet is rapidly resuspended in 12 mLof ice-cold H₂O for red blood cell lysis to occur. After 20 seconds, 4mL of ice-cold 0.6 M KCl is added. Samples are mixed carefully andcentrifuged for 6 minutes at 1300 rpm, 4° C. The supernatant isdiscarded and the red blood cell lysis procedure is repeated one moretime. Subsequently, the cell pellet is resuspended in 4 mL of DPBS andlayered over 5 mL of Lymphoprep (Nycomed Pharma, Cat. No.: 1114545) in a15 mL centrifuge tube. After centrifugation for 12 min at 1300 rpm, 4°C., the supernatant is removed and the cell pellet, containing theneutrophils, is resuspended in 25 mL chemotaxis buffer (RPMI 1640medium, supplemented with 10 mM HEPES; freshly made for each experiment)

2.1.2 Migration Assay

A cell suspension of 8.9×10⁶ cells per milliliter is prepared. 20 μL ofcompound solution in chemotaxis buffer is added to 180 μL cellsuspension. The mixture is incubated at 37° C. for 30 minutes withintermediate resuspension of the cells after 15 minutes. Following this,70 μL cell suspension is transferred to the upper compartment of aCorning HTS transwell 96 permeable support system with 5.0 μm pore sizepolycarbonate membrane (Corning, Cat. No.: 3387). The receiver well ofthe transwell system is then filled with 200 μL chemotaxis buffercontaining compound and chemotactic agent (embelin). After incubation at37° C. in 5% CO₂ for 1 h, the upper plate of the transwell system isremoved and the cell suspension in the receiver plate is transferred toa 96-well V-bottom plate. 50 μL of DPBS is added to the receiver plateto prevent remaining cells from drying out. The V-bottom plate iscentrifuged for 6 minutes at 1500 rpm. The supernatant is removed andthe cells are resuspended in 50 μL DPBS. The cells are then transferredback to the receiver plate of the transwell system. After this, 100 μLATPlite solution (Perkin Elmer, Cat. No.: 436110) was added to thecells. The plate is incubated for 10 minutes in the dark, while shaking.170 μL of cell lysate is then transferred to a white 96-well plate andluminescence is measured. The detected luminescent signal is consideredas linearely related to the number of cells having migrated from theupper well to the receiver well.

TABLE VII human neutrophil migration inhibition Cpd# Neutrophils 4 *** 7*** 8 *** 9 **** 16 *** 17 **** 19 **** 20 **** 22 **** 23 *** 30 ****34 **** 35 *** 36 *** 41 **** 42 *** 52 **** 56 *** 60 **** 62 **** 63**** 68 **** 69 **** 72 **** 77 **** 80 **** 83 **** 85 **** 89 **** 90**** 92 **** 98 **** 107 **** 109 **** 111 **** 112 **** 114 **** 115**** 116 **** 121 *** 122 **** 123 **** 126 **** 133 **** 139 **** 140**** 147 **** 149 **** 150 **** 158 **** 159 **** 160 *** 161 **** 168**** 169 **** 170 **** 171 **** 174 **** * >1001 nM ** 501-1000 nM ***101-500 nM **** 0.01-100 nM

2.2. Rat Neutrophil Migration Assay

We have established that GPR84 agonists (MCFA such as sodiumdecanoate,3,3′ di indolylmethane and Embelin induce neutrophil chemotaxis and thatGPR84 antagonists could block GPR84 agonist-induced chemotaxis but notIL8-induced chemotaxis, indicating that G Protein-Coupled Receptor 84(GPR84) is an essential player in the process of neutrophil recruitment.

The effect of agonists or antagonists for GPR84 can therefore be assayedin a neutrophil migration test. In the rat neutrophil migration assay,neutrophils, freshly isolated from rat after intraperitoneal injectionof glycogen (0.1%, w/v), are treated with a compound for 30 minutes.Subsequently, the neutrophils are transferred to the upper wells of aCorning HTS transwell 96 permeable support system, of which the lowerwells are filled with a embelin solution at EC80 (concentration whichgive 80% of the activity of the GPR84). After 1 h of incubation,migration of the neutrophils towards embelin in the lower compartmentcan be quantified by measuring the ATP-content of the lower wells usingthe Cell Titer Glow Substrate assay system (Promega, Cat.No.: G755B).

2.2.1. Isolation of Neutrophils from Rats

24 h after intraperitoneal injection of glycogen (0.1%, w/v), cells areharvested by peritoneal lavage with 25 mL HBSS then centrifuged for 12minutes at 1300 rpm and 4° C. After centrifugation, the supernatant isdiscarded and the remaining cell pellet is rapidly resuspended in 12 mLof ice-cold H₂O for red blood cell lysis to occur. After 20 seconds, 4mL of ice-cold 0.6 M KCl is added. Samples are mixed carefully andcentrifuged for 6 minutes at 1300 rpm, 4° C. The supernatant isdiscarded and the cell pellet is resuspended in 4 mL of DPBS and layeredover 5 mL of Lymphoprep (Axis Shield, Cat. No.: 1114544) in a 15 mLcentrifuge tube. After centrifugation for 30 min at 1500 rpm, 4° C., thesupernatant is removed and the cell pellet, containing the neutrophils,is resuspended in 5 mL chemotaxis buffer (RPMI 1640 medium, supplementedwith 10 mM HEPES; freshly made for each experiment).

2.2.2. Migration Assay

A cell suspension of 8.9×106 cells per milliliter is prepared. 10 μL ofcompound solution in chemotaxis buffer is added to 90 μL cellsuspension. The mixture is incubated at 37° C. for 30 minutes withintermediate resuspension of the cells after 15 minutes. Following this,75 μL cell suspension is transferred to the upper compartment of aCorning HTS transwell 96 permeable support system with 5.0 μm pore sizepolycarbonate membrane (Corning, Cat.No.: 3387). The receiver well ofthe transwell system is then filled with 200 μL chemotaxis buffercontaining compound and chemotactic agent (embelin). After incubation at37° C. in 5% CO2 for 1 h, the upper plate of the transwell system isremoved and 70 μL Cell Titer Glow Substrate (Promega, Cat.No.: G755B)are added in the receiver plate. The receiver plate is incubated for 10minutes in the dark, while shaking. 180 μL of cell lysate is thentransferred to a white 96-well plate and luminescence is measured. Thedetected luminescent signal is considered as linearely related to thenumber of cells having migrated from the upper well to the receiverwell.

3. ADME, PK and Safety Models

3.1 Aqueous Solubility

Starting from a 10 mM stock in DMSO, a serial dilution of the compoundis prepared in DMSO. The dilution series is transferred to a 96 NUNCMaxisorb plate F-bottom and 0.1M phosphate buffer pH 7.4 or 0.1M citratebuffer pH3.0 at room temperature is added.

The final concentrations range from 18.75 to 300 μM in 5 equal dilutionsteps. The final DMSO concentration does not exceed 3%.

200 μM Pyrene is added to the corner points of each 96 well plate andserves as a reference point for calibration of Z-axis on the microscope.

The assay plates are sealed and incubated for 1 h at 37° C. whileshaking at 230 rpm. The plates are then scanned under a white lightmicroscope, yielding individual pictures of the precipitate perconcentration. The precipitate is analyzed and converted into a numberby a custom-developed software tool. The first concentration at whichthe compound appears completely dissolved is the concentration reported,however the true concentration lies somewhere between this concentrationand one dilution step higher.

Solubility values are reported in μM and in μg/mL.

3.2. Thermodynamic Solubility

Two individual solutions of 2 mg/mL of compound are prepared in a 0.1 Mphosphate buffer pH 7.4 or a 0.1 M citrate buffer pH 3.0 at roomtemperature in a 2 mL glass vial.

After addition of a magnetic stir, the samples are stirred at roomtemperature for 24 h.

After 24 h, the vials are centrifuged 10 min at 1400 rpm. Thesupernatant of the sample is then transferred to a MultiscreenRSolubility Plate (Millipore, MSSLBPC50) and filtered (10-12″ Hg) withthe aid of a vacuum manifold into a clean Greiner polypropylene V-bottom96 well plate. Per sample, two dilutions (factor 10 and 100) are made inDMSO. Other dilutions can be made if the acquired peak area is notwithin the standard curve.

A 10 mM DMSO stock, made from dry matter, is used to make a 200 μg/mLworking stock. The standard curve for the compound is prepared in DMSOstarting from the 200 μg/mL working stock. Eight concentrations and twoquality control samples (QC) are made in 2 mL tubes. The first 3concentrations (50, 35 and 15 μg/mL) and the first QC sample (20 μg/mL)are made starting with the 200 μg/mL working stock. The 4^(th)concentration (5 μg/mL) is made with the 50 μg/mL solution and the5^(th) concentration (1 μg/mL) with the 15 μg/mL. The last threeconcentrations (0.2, 0.1 and 0.05 μg/mL) are made with the 1 μg/mLsolution. The second QC sample (0.5 μg/mL) is made with the first QCsample.

Of every step of the dilution series, quality control and sampledilutions, a volume is transferred to a 96-well Deepwell plate. Thesamples are injected on a LC-MS/MS system (API2000 from AppliedBiosystems).

The samples are analyzed on LC-MS/MS with a flow rate of 0.5 mL/min.Solvent A is 0.1% Formic Acid in water and solvent B is 0.1% Formic Acidin methanol. The sample is run under positive ion spray on a Pursuit 5C18 2.0 mm column (Varian). The solvent gradient has a total run time of1.4 minutes and ranges from 10% B to 100% B.

The thermodynamic solubility samples are analyzed with the aid ofQuanLynx software. For the standard curve a linear or quadratic curvecan be used in the analysis. Samples of the standard curve that havemore than 15% deviation are excluded; the lowest concentrations of thecurve may vary up to 20%. Peak areas of the samples are plotted againstthe standard curve to obtain the solubility of the compound.

Solubility values are reported in μM or μg/mL.

3.3 Microsomal Stability

A 10 mM stock solution of compound in DMSO is 1,668 fold diluted in a105 mM phosphate buffer pH 7.4. Of this compound dilution, 50 μL istransferred in two 96 assay plates: one for time point 0 min (T0 plate)and one for time point 30 min (T30 plate) and pre-warmed at 37° C.

In the time zero reference sample (TO plate), 100 μL MeOH (1:1) is addedto the wells. In each assay plate (T0 and T30 min), 50 μL of microsomalmix is then added.

Final reaction concentrations are: 3 μM compound, 0.5 mg/mL microsomes,0.4 U/mL GDPDH, 3.3 mM MgCl₂, 3.3 mM glucose-6-phosphate and 1.3 mMNADP⁺.

The T30 plate is incubated at 37° C., 300 rpm and after 30 minutes ofincubation the reaction is stopped with MeOH (1:1). The samples aremixed, centrifuged and the supernatant is harvested for analysis onLC-MS/MS (API2000 from Applied Biosystems).

The samples are analyzed on LC-MS/MS with a flow rate of 0.5 mL/min.Solvent A is 0.1% Formic Acid in water and solvent B is 0.1% Formic Acidin methanol. The sample is run under positive ion spray on a Pursuit 5C18 2.0 mm column (Varian). The solvent gradient has a total run time of1.4 minutes and ranges from 10% B to 100% B. Peak area from the parentcompound at time 0 is considered to be 100% remaining. The percentageremaining after 30 minutes incubation is calculated from time 0 Thesolubility of the compound in the final test concentration in buffer isinspected by microscope and results are also reported.

3.4 Hepatocyte Stability.

Test compounds (1 μM initial concentration, n=2) are incubated inWilliams' Medium E, containing 4 mM L-gutamine and 2 mM magnesiumsulphate, with pooled cryopreserved hepatocytes (Celsis International)in suspension at cell densities of 0.25-0.5 million viable cells/mL. Theincubations are performed at 37° C. in a shaking water bath with 100 μLsamples taken from the incubation at 0, 10, 20, 45 and 90 minutes, andreactions terminated by addition of 100 μL of acetonitrile containingcarbamazepine as analytical internal standard. Samples are centrifugedand the supernatant fractions analysed by LC-MS/MS. The instrumentresponses (i.e. peak heights) are referenced to the zero time-pointsamples (as 100%) in order to determine the percentage of compoundremaining Ln plots of the % remaining for each compound are used todetermine the half-life for the hepatocyte incubations. Half-life valuesare calculated from the relationship: T_(1/2) (min)=−0.693/λ, where λ isthe slope of the Ln concentration vs time curve. Standard compoundstestosterone, midazolam, and 4-methylumbelliferone are included in theassay design.

3.5 Plasma Protein Binding (Equilibrium Dialysis)

A 10 mM stock solution of the compound in DMSO is diluted with a factor10 in DMSO. This solution is further diluted in freshly thawed human,rat, mouse or dog plasma (BioReclamation INC) with a final concentrationof 5 μM and final DMSO concentration of 0.5%.

A Pierce Red Device plate with inserts (ThermoScientific) is preparedand filled with 450 μL PBS in the buffer chamber and 300 μL of thespiked plasma in the plasma chamber. The plate is incubated for 4 h at37° C. while shaking at 100 rpm. After incubation, 120 μL of bothchambers is transferred to 480 μL methanol in a 96-well round bottom, PPdeep-well plates (Nunc) and sealed with an aluminum foil lid. Thesamples are mixed and immediately centrifuged 30 min at 1400 rcf at 4°C. and the supernatant is transferred to a 96 v-bottom PP plate(Greiner, 651201) for analysis on LC-MS/MS (API2000 from AppliedBiosystems).

The samples are analyzed on LC-MS/MS with a flow rate of 0.5 mL/min.Solvent A is 0.1% Formic Acid in water and solvent B is 0.1% Formic Acidin methanol. The sample is run under positive ion spray on a Pursuit 5C18 2.0 mm column (Varian). The solvent gradient has a total run time of1.4 minutes and ranges from 10% B to 100% B.

Peak area from the compound in the buffer chamber and the plasma chamberare considered to be 100% compound. The percentage bound to plasma isderived from these results and is reported as percentage bound toplasma.

The solubility of the compound in the final test concentration in PBS isinspected by microscope to indicate whether precipitation is observed ornot.

3.6 Caco2 Permeability

Bi-directional Caco-2 assays are performed as described below. Caco-2cells are obtained from European Collection of Cell Cultures (ECACC, cat86010202) and used after a 21 day cell culture in 24-well Transwellplates (Corning, cell growth area: 0.33 cm², Membrane pore size: 0.4 μM,membrane diameter: 6.5 mm).

2×10⁵ cells/well are seeded in plating medium consisting ofDMEM+GlutaMAX™-I+1% NEAA+10% FBS (FetalClone II)+1% Pen/Strep. Themedium is changed every 2-3 days.

Test and reference compounds (propranolol and rhodamine-123 orvinblastine, all purchased from Sigma) are prepared in Hanks' BalancedSalt Solution containing 25 mM HEPES (pH7.4) and added to either theapical (125 μL) or basolateral (600 μL) chambers of the Transwell plateassembly at a concentration of 10 μM with a final DMSO concentration of0.25%.

50 μM Lucifer Yellow (Sigma) is added to the donor buffer in all wellsto assess integrity of the cell layers by monitoring Lucifer Yellowpermeation. As Lucifer Yellow (LY) cannot freely permeate lipophilicbarriers, a high degree of LY transport indicates poor integrity of thecell layer.

After a 1 h incubation at 37° C. while shaking at an orbital shaker at150 rpm, 70 μL aliquots are taken from both apical (A) and basal (B)chambers and added to 100 μL 50:50 acetonitrile:water solutioncontaining analytical internal standard (0.5 μM carbamazepine) in a 96well plate.

Lucifer yellow is measured with a Spectramax Gemini XS (Ex 426 nm and Em538 nm) in a clean 96 well plate containing 150 μL of liquid frombasolateral and apical side.

Concentrations of compound in the samples are measured by highperformance liquid-chromatography/mass spectroscopy (LC-MS/MS).

Apparent permeability (P_(app)) values are calculated from therelationship:P _(app)=[compound]_(acceptor final) ×V_(acceptor)([compound]_(donor initial) ×V _(donor))T _(inc) ×V_(donor)/surface area×60×10⁻⁶ cm/s

-   V=chamber volume-   T_(inc)=incubation time.-   Surface area=0.33 cm²

The Efflux ratios, as an indication of active efflux from the apicalcell surface, are calculated using the ratio of P_(app) B>A/P_(app) A>B.

The following assay acceptance criteria are used:

-   Propranolol: P_(app) (A>B) value≧20(×10⁻⁶ cm/s)-   Rhodamine 123 or Vinblastine: P_(app) (A>B) value □<5 (×10⁻⁶ cm/s)    with Efflux ratio≧5.-   Lucifer yellow permeability: ≦100 nm/s

3.7 Liability for QT Prolongation

Potential for QT prolongation is assessed in the hERG manual patch clampassay.

3.7.1 Conventional Whole-cell Patch-clamp

Whole-cell patch-clamp recordings are performed using an EPC10 amplifiercontrolled by Pulse v8.77 software (HEKA). Series resistance istypically less than 10 MΩ and compensated by greater than 60%,recordings are not leak subtracted. Electrodes are manufactured fromGC150TF pipette glass (Harvard).

The external bathing solution contains: 135 mM NaCl, 5 mM KCl, 1.8 mMCaCl₂, 5 mM Glucose, 10 mM HEPES, pH 7.4.

The internal patch pipette solution contains: 100 mM Kgluconate, 20 mMKCl, 1 mM CaCl₂, 1 mM MgCl₂, 5 mM Na₂ ATP, 2 mM Glutathione, 11 mM EGTA,10 mM HEPES, pH 7.2.

Drugs are perfused using a Biologic MEV-9/EVH-9 rapid perfusion system.

All recordings are performed on HEK293 cells stably expressing hERGchannels. Cells are cultured on 12 mm round coverslips (German glass,Bellco) anchored in the recording chamber using two platinum rods(Goodfellow). hERG currents are evoked using an activating pulse to +40mV for 1000 ms followed by a tail current pulse to −50 mV for 2000 ms,holding potential is −80 mV. Pulses are applied every 20 s and allexperiments are performed at room temperature.

3.7.2 Data Analysis

IC₅₀ values are calculated for each compound tested. The fold differencebetween the IC₅₀ in the manual hERG patch clamp and the unbound IC₅₀ inthe whole blood assay is calculated.

For the concentration response curves, peak tail current amplitude ismeasured during the voltage step to −50 mV. Curve-fitting ofconcentration-response data is performed using the equation:y=a+[(b−a)/(1+10^((log c−x)d)]

where a is minimum response, b is maximum response and d is Hill slope,this equation can be used to calculate both IC₅₀ (where y=50 and c isthe IC₅₀ value) and IC₂₀ (where y=20 and c is the IC₂₀ value). GraphPad®Prism® (Graphpad® Software Inc.) software is used for all curve fitting.A difference of 100 fold or greater indicates a low potential for QTprolongation.

3.8 Pharmacokinetic Study

3.8.1 Single Dose Pharmacokinetic Study in Rats

Compounds are formulated in PEG200/physiological saline mixtures for theintravenous route and in PEG400/0.5% methylcellulose (10/90 v/v) for theoral route. Test compounds are orally dosed as a single esophagealgavage at 5-10 mg/kg and intravenously dosed as a bolus via the caudalvein at 1 mg/kg to male Sprague-Dawley rats. Each group consists of 3rats. Blood samples are collected either via the jugular vein usingcannulated rats or at the retro-orbital sinus with lithium heparin asanti-coagulant at the time points in the following range: 0.05 to 8 h(intravenous route), and 0.25 to 6 or 24 h (oral route). Whole bloodsamples are centrifuged at 5000 rpm for 10 min and the resulting plasmasamples are stored at −20° C. pending analysis.

3.8.2 Multiple Dose Pharmacokinetic Study in Rats

Compounds are formulated in PEG400/0.5% methylcellulose (10/90 v/v) forthe oral route. Test compounds are orally dosed as an esophageal dailygavage at 30 or 300 mg/kg to male Sprague-Dawley rats for 14 days. Eachgroup consists of 3 rats. Blood samples are collected via the tail veinwith lithium heparin as anti-coagulant at the following time points onday 1, 7 and 14: 0.25, 1, 4, 8 and 24 h. In addition, on day 2 bloodsamples are taken at 0.25, 1 and 4 h and at day 4 and 11 at 0.25 h.Whole blood samples are centrifuged at 5000 rpm for 10 min and theresulting plasma samples are stored at −20° C. pending analysis.

3.8.3 Quantification of Compound Levels in Plasma

Plasma concentrations of each test compound are determined by anLC-MS/MS method in which the mass spectrometer is operated in positiveor negative electrospray mode.

3.8.4 Determination of Pharmacokinetic Parameters

Pharmacokinetic parameters are calculated using Winnonlin® (Pharsight®,US).

3.9 7-Day Rat Toxicity Study

A 7-day oral toxicity study with test compounds is performed inSprague-Dawley male rats to assess their toxic potential andtoxicokinetics, at daily doses of 100, 300 and 1000 mg/kg/day, bygavage, at the constant dosage-volume of 10 mL/kg/day.

The test compounds are formulated in PEG400/0.5% methylcellulose (10/90,v/v). Each group includes 6 principal male rats as well as 3 satelliteanimals for toxicokinetics. A fourth group is given PEG400/0.5%methylcellulose (10/90, v/v) only, at the same frequency, dosage volumeand by the same route of administration, and acts as the vehicle controlgroup.

The goal of the study is to determine the lowest dose that results in noadverse events being identified (no observable adverse effectlevel—NOAEL).

3.10 Cytochrome P450 Inhibition

Reversible CYP inhibition and time-dependent CYP3A4 inhibition isdetermined in human liver microsomes and specific probe substrates.

3.10.1 P450 Inhibition in Human Liver Microsomes, Reversible Inhibition

The inhibitory potential of a test compound is assessed for humancytochrome P450 isoenzymes CYP1A2, 2C8, 2C9, 2C19, 2D6 and 3A4.

A 10 mM stock solution of the test compound is prepared in DMSO,serially diluted in Tris buffer (100 mM pH 7.4) and added to hepaticmicrosomes (Xenotech LLC) and NADPH at 37° C. in a shaking water bath.Seven different test compounds concentrations (0.05 to 100 μM), 1% DMSOand 1 mM NADPH are obtained to react.

After 15 or 30 minutes reactions are terminated by addition of 100 μL ofacetonitrile containing carbamazepine as analytical internal standard.Samples are centrifuged and the supernatant fractions analysed byLC-MS/MS. For each isoform, the instrument responses (peak heights) arereferenced to those for DMSO controls (considered as 100%) in order todetermine the percentage reduction in probe metabolism, using midazolamand testosterone as probe substrate. Percentage inhibition of probemetabolism and Log [test compound concentration] are plotted usingGraphpad Prism software. The sigmoidal dose response model is fitted tothe data in order to determine the IC₅₀.

Inhibition of CYP3A4 using nifedipine and atorvastatin as probesubstrate is carried out as follows.

A 1.67 mM stock solution of test compound is prepared in methanol,serially diluted 1:3 in 50 mM potassium phosphate buffer pH7.4 and addedto human hepatic microsomes (BD Gentest) and probe substrate. Sevendifferent test compounds concentrations (0.045-33.3 μM), 2% methanol,0.1 mg/mL microsomes, 10 μM atorvastatin or 5 μM nifedipine. Afterpre-warming 5 minutes at 37° C., the reaction was started by addingcofactor mix (7.65 mg/mL glucose-6-phosphate, 1.7 mg/mL NADP, 6 U/mL ofglucose-6-phosphate dehydrogenase).

After 5 min (nifedipine) or 10 min (atorvastatin) at 37° C., thereaction (50 μL) is terminated with 150 μL acetonitrile:methanol (2:1)solution with internal standard (Warfarin). Samples are centrifuged andthe supernatant fractions analyzed by LC-MS/MS. The instrument responses(ratio of test compound/internal standard peak areas) are referenced tothose for solvent controls (assumed as 100%) in order to determine thepercentage reduction in probe metabolism. Percent of control activity vsconcentration plots are generated and fitted using GraphPad Prismsoftware to generate IC₅₀.

3.10.2 CYP3A4 Inhibition in Human Liver Microsomes, Time-dependent

The time-dependent inhibitory potential of a test compound is assessedfor human cytochrome P450 isoenzyme 3A4. The compound is pre-incubatedwith the human liver microsomes before addition of the probe substrates.The result is compared to the condition where the compound is notpre-incubated with the human liver microsomes to see if there was ashift in IC₅₀, indicating time-dependent inhibition.

A 10 mM stock solution of test compound is prepared in DMSO and diluted1:20 with Tris buffer (100 mM pH 7.4) and further serially diluted inTris buffer/5% DMSO.

The cofactor, NADPH, and each test compound dilution is mixed in twoseparate plates for 0 and 30 min pre-incubation. Human hepaticmicrosomes (Xenotech LLC) are added only to the “30 minutepre-incubation” plate and both plates are then incubated for 30 minutesat 37° C. in a shaking water bath. Following the pre-incubation,microsomes are added to the “0 minute” plate and appropriate probesubstrates (in 0.5% DMSO) are added to both plates. Plates are thenreturned to the water bath for a further incubation.

In total, six different test compound concentrations (1.6 to 50 μM) areassessed. Reactions are terminated with 100 μL of acetonitrilecontaining carbamazepine as analytical internal standard. Samples arecentrifuged and the supernatant fractions analysed by LC-MS/MS. For eachisoform, the instrument responses (peak height ratio with internalstandard) are referenced to those for DMSO controls (considered as 100%)in order to determine the percentage reduction in probe metabolism.Percentage inhibition of probe metabolism and Log [Test Compoundconcentration] are plotted using Graphpad Prism software. The sigmoidaldose response model is fitted to the data in order to determine theIC₅₀.

4. In-vivo Studies

The in-vivo activity of the compounds of the invention may bedemonstrated in the following in vivo efficacy inflammation models.

4.1 Inflammatory Bowel Disease (Mice).

The mouse chronic DSS-induced inflammatory bowel disease model (IBD) isa well validated disease model for inflammatory bowel disease (Wirtz S.et al., 2007 Nature Protocols 2, 541-546; Sina C. et al., 2009 J.Immunol. 183 7514-7522).

To induce a chronic colitis, female BALB/c mice are fed with 4% dextransodium sulfate (DSS) dissolved in drinking water for 4 days, followed by3 days of regular drinking water. This cycle is repeated three times.This protocol allows inducing a strong colitis while avoiding highmortality rates. Animals are divided into several groups:

a. intact water; vehicle alone, n=10),

b. diseased (DSS; vehicle alone, n=10),

c. sulfazalazine used as reference (DSS; 20 mg/kg/day, p.o., n=10) and

d. the tested compound (DSS; 1, 3, 10, 30 mg/kg/day, p.o., n=10).

Clinical parameters are measured every other day. The disease activityindex (DAI) is a composite measure combining of the individual scoresfor weight loss, stool consistency and rectal bleeding. Mice aresacrificed at day 20 of the experiment according to the protocolintroduced by Sina et al. (2009). At sacrifice time, the complete colonis removed and rinsed with sterile PBS. Segments of the distal colon aredissected for histological analysis, gene expression and protein levelmeasurement.

4.2 Collagen-induced Arthritis (Mice).

The mouse collagen-induced arthritis (CIA) is the gold standardrheumatoid arthritis model (Brand, et al., 2007 Nature Protocols 2,1269-1275, Lin et al., 2007 Br J Pharmacol 1, 829-831). DBA1//J malemice are injected with a collagen II solution (Completed Freund'sadjuvant) Immune reaction is boosted by a second injection (incompleteFreund's adjuvant) 21 days later. At day 31, arthritis is scoredaccording to the method of Khachigian et al. (Khachigian et al., 2006Nature Protocols 1, 2512-2516) and animals are randomized to reach anaverage clinical score of 2 per group Animals are divided into severalgroups: intact (no treatment, n=5), diseased (vehicle alone, n=10),Enbrel® as reference (10 mg/kg, 3× week, i.p., n=10), and the testedcompound (3, 10 or 30 mg/kg/day, p.o., n=10). Therapeutic dosing lastedfrom day 31 to day 46 and the arthritis is scored every day. Mice aresacrificed at day 46, X-ray photos are taken of the hind paws of eachindividual animal and the severity of bone erosion is ranked with theradiological Larsen's score (Salvemini et al., 2001 Arthritis Rheum 44,2909-2921).

4.3 Tabacco Smoke Model (Mice)

Daily exposures of female inbred C57BL/6J mice to tobacco smoke (TS) for11 consecutive days result in pulmonary inflammation, as indicated by anincrease in the total number of cells recovered in the bronchoalveolarlavage (BAL), when compared with a similarly treated air-exposed group,24 h after the final exposure. The exposure period to TS is increasedinitially from 25 minutes at the start of the study (day 1) to a maximumof 45 minutes on day 3 until day 11. Animals are divided into severalgroups: intact (no treatment, n=5), diseased (vehicle alone, n=10),Roflumilast as reference (5 mg/kg/day p.o., n=10), and the testedcompounds (10 or 30 mg/kg/bid, p.o., n=10). At the end of 11 days, thenumbers of macrophages, epithelial cells, neutrophils and lymphocytesare counted in the BAL. BAL is further analysed for gene expression andprotein level. Lung tissue is dissected for histological analysis, geneexpression and protein level measurement.

It will be appreciated by those skilled in the art that the foregoingdescriptions are exemplary and explanatory in nature, and intended toillustrate the invention and its preferred embodiments. Through routineexperimentation, an artisan will recognise apparent modifications andvariations that may be made without departing from the spirit of theinvention. All such modifications coming within the scope of theappended claims are intended to be included therein. Thus, the inventionis intended to be defined not by the above description, but by thefollowing claims and their equivalents.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

It should be understood that factors such as the differential cellpenetration capacity of the various compounds can contribute todiscrepancies between the activity of the compounds in the in vitrobiochemical and cellular assays.

At least some of the chemical names of compound of the invention asgiven and set forth in this application, may have been generated on anautomated basis by use of a commercially available chemical namingsoftware program, and have not been independently verified.Representative programs performing this function include the Lexichemnaming tool sold by Open Eye Software, Inc. and the Autonom Softwaretool sold by MDL, Inc. In the instance where the indicated chemical nameand the depicted structure differ, the depicted structure will control.

Chemical structures shown herein were prepared using either ChemDraw® orISIS®/DRAW. Any open valency appearing on a carbon, oxygen or nitrogenatom in the structures herein indicates the presence of a hydrogen atom.Where a chiral center exists in a structure but no specificstereochemistry is shown for the chiral center, both enantiomersassociated with the chiral structure are encompassed by the structure.

REFERENCES

-   Wittenberger et al., 2001 J Mol Biol, 307, 799-813-   Yousefi S et al., 2001 J Leukoc Biol, 69, 1045-52-   Wang et al., 2006 The Journal of Biological Chemistry, 281, 45,    34457-34464-   Venkataraman et al., 2005, Immunology Letters, 101, 144-153-   WO2007/027661 A2-   Berry et al., 2010, Nature, 466, 973-979-   Bouchard et al., 2007, Glia, 55:790-800-   Bundgard, H., 1985 Design of Prodrugs, pp. 7-9, 21-24, Elsevier,    Amsterdam 1985-   Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985,    Mack Publishing Company, Easton, Pa.-   T. W. Greene and P. G. M. Wuts, 2006 Protecting Groups in Organic    Synthesis, Wiley-Blackwell; 4th Revised edition-   Young Kim et al., 2007 Bioorganic & Medicinal Chemistry 15,    2667-2679-   Le Pouls et al., 2003, The Journal of Biological Chemistry, 278, 28,    25481-25489-   Brown et al., 2003, The Journal of Biological Chemistry, 278, 13,    11312-11319-   Stoddart et al., 2008, Pharmacological Reviews, 60, 405-417-   Wirtz S. et al., 2007 Nature Protocols 2, 541-546-   Sina C. et al., 2009 J. Immunol. 183 7514-7522-   Brand, et al., 2007 Nature Protocols 2, 1269-1275-   Lin et al., 2007 Br J Pharmacol 1, 862-872-   Khachigian et al., 2006 Nature Protocols 1, 2512-2516-   Salvemini et al., 2001 Arthritis Rheum 44, 2909-2921-   Du Bois, 2010, Nat Rev, Drug Discovery, 9, 129-   Nagasaki et. al., 2012, FEBS Letters, 586, 368-372

What is claimed:
 1. A compound according to Formula IIIa:

wherein L₁ is absent; W is C₁₋₄ alkylene, C₂₋₄ alkenylene having onedouble bond, or C₂₋₄ alkynylene having one triple bond; L₂ is absent oris —O—; R² is C₃₋₇ cycloalkyl optionally substituted with one R⁵ group,R⁵ is oxo or R⁶; and R⁶ is selected from OH and C₁₋₆ alkyl, or apharmaceutically acceptable salt, or a solvate, or a solvate of thepharmaceutically acceptable salt thereof.
 2. A compound orpharmaceutically acceptable salt thereof, according to claim 1, whereinW is C₂₋₄ alkynylene having one triple bond.
 3. A compound orpharmaceutically acceptable salt thereof, according to claim 1, whereinR² is C₃₋₇ cycloalkyl.
 4. A compound or pharmaceutically acceptable saltthereof, according to claim 1, wherein the compound is selected from:9-Cyclopentylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,2([1,4]Dioxan-2-ylmethoxy)-9-(1-hydroxy-cyclopentylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,9-Cyclopentyloxymethyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,9-Cyclopentyloxymethyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,9-Cyclopropylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,9-Cyclopropylethyl-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,9(2-Cyclopropyl-ethynyl)-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,9-Cyclopentyloxymethyl-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,9(2-Cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,9-Cyclopentyloxymethyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,and2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one.5. A pharmaceutical composition comprising a compound orpharmaceutically acceptable salt thereof, according to claim 1, and apharmaceutically acceptable carrier.
 6. The pharmaceutical compositionaccording to claim 5 comprising a further therapeutic agent.
 7. Acompound or pharmaceutically acceptable salt thereof, according to claim1, wherein R² is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 8.A compound or pharmaceutically acceptable salt thereof, according toclaim 1, wherein the compound is according to Formula Va:

wherein R² is C₃₋₇ cycloalkyl optionall substituted with one R⁵ group,R⁵ is oxo or R⁶; and R⁶ is selected from —OH and C₁₋₆ alkyl.
 9. Acompound or pharmaceutically acceptable salt thereof, according to claim1, wherein the compound is according to Formula Vb:

wherein R² is C₃₋₇ cycloalkyl optionally substituted with one R⁵ group;R⁵ is oxo or R⁶; and R⁶ is selected from —OH and C₁₋₆ alkyl.